>> GOOD AFTERNOON. SO TODAY YOU ALL KNOW IS IDES OF MARCH SHAKESPEAREANs KNOW THAT THAT'S WHEN JULIUS CAESAR MET HIS END. NOT THAT WE'RE CONTEMPLATING ANYTHING LIKE THAT, BUT AT ANY RATE, I THOUGHT I WOULD WILL SAY IT. SO WE HAVE 2 PEOPLE WHO HAVE NOT BEEN HERE BEFORE, SO LET ME REMIND YOU WHAT THIS IS? DO YOU KNOW WHAT THIS IS? WHAT IS IT? WHAT IS IT? ANYBODY? IT'S THE BROOKLYN BRIDGE. SO IT'S THE MOST FAMOUS BRIDGE IN THE WORLD. SO WHY DO WE SHOW THE BROOKLYN BRIDGE? BECAUSE IT SYMBOLIZES THE WHOLE PURPOSE OF THIS COURSE, WHICH IS TO DEAL WITH WHAT MANY OF US THINK IS THE BIGGEST PROBLEM IN SCIENCE TODAY WHICH IS NOT NEW TECHNOLOGY AND IT ISN'T EVEN NEW DRUGS, IT'S COMMUNICATION. THE IT'S THE GREAT ADVANCES IN BASIC BIOLODGEICAL ENGINEERING SCIENTISTS WHICH YOU CAN MAKE BELIEVE ARE TAKING PLACE ON THAT SIDE OF THE RIVER WHICH IS MANHATTAN AND THEN THERE'S CRIP CLINICAL MEDICINE, PATIENTS DISEASE AND SO FORTH WHICH IS ON THIS SIDE OF THE BRIDGE WHICH IS BROOKLYN. AND THE REAL NAME OF THE GAME IS HOW TO GET PEOPLE TO TALK TOGETHER. THE OTHER INTERESTING THING OF COURSE IS ONCE YOU BUILD THE BRIDGE, LIFE IS NEVER THE SAME ON EITHER SIDE. SO WHAT WE TRY TO DO IS TO COMBINE IN THIS PROGRAM, USUALLY WHEN WE CAN A LIVE PATIENT WHO MOST OF YOU HEAR LAST WEEK WILL RECALL FIB OR 10 MINUTES DESCRIBES WHAT IT'S LIKE TO HAVE THE DISEASE THEY HAVE, PUTS A HUMAN FACE ON DISEASE AS SOMEONE PUT IT. AND THEN SOMEONE WHO'S A PHYSICIAN CLINICAL TRANSLATION INVESTIGATOR WHO TALKS THROUGH MAINLY BASIC SCIENCES OR MOST OF THE THINGS ABOUT FUNDAMENTAL THINGS YOU SHOULD KNOW ABOUT THE DISEASE. THINGS YOU CAN READILY UNDERSTAND WITHOUT HAVING TAKEN A SPECIALIZED COURSE, THINGS LIKE EPIDEMIOLOGY, HOW TO KNOW WHETHER SOMEBODY HAS IT, WHERE DO WE STAND, THE DIAGNOSIS AND WHY THAT PERSON IS HERE AT THE NIH SPENDING THEIR CAREER DOING EXCITING STUFF AND WHAT ARE THE CHALLENGES AND THERE'S PLENTY OF ROOM FOR COMMENTS, QUESTIONS AND DISCUSSIONS AND WE ENCOURAGE YOU, PARTICULARLY MEDICAL JARGON STARTS FLYING AROUND AND YOU DON'T UNDERSTAND, SAY HEY, WAIT A MINUTE AND WE'LL START OVER AGAIN. MENT AND THEN THE SECOND SPEAKER IS SOMEONE WHO'S MORE AS A BASIC SCIENTIST DEALING WITH FUNDAMENTAL MECHANISMS THAT ARE INVOLVED IN SOME ASPECTS OF IT. NOW TODAY, WE HAVE A SPECIAL TREAT BECAUSE I WILL START BY INTRODUCING THE SECOND SPEAKER FIRST. SO THE SPEAKER IS ROSANA KAPELLER, SHE GRADUATED FROM HER NATIVE SCHOOL IN BRAZIL AND RECEIVED HER Ph.D. DEGREE IN THE DEPARTMENT I WAS THE CHAIRMAN OF AT TUFTS IN BOSTON, MOLECULAR AND CELLULAR PHYSIOLOGY AND SHE TRAINED WITH AND THEN ROSANA AFTER HER POST DOCTORAL FELLOWSHIP AT DANA-FARBER, GOT INTERESTED IN IF ANOTHER ASPECT AND THAT IS, I DON'T WANT TO CALL IT THE COMMERCIAL BUT THAT'S REALLY WHAT IT IS. IT'S THE EXPLOSIONS THAT WERE TAKING PLACE WITH BIOTECH COMPANIES BEING FORMED AND DEALING WITH NEW PRODUCTS AND NEW IDEAS, VENTURE CAPITALISTS AND SO FORTH AND ROSANA IS 1 OF THE MOST SUCCESSFUL AND ENERGETIC PEOPLE IN BRIDGING IN FIELD AND SO THIS IS A DIFFERENT KIND OF BRIDGING. IT'S A TOP NOTCH BASIC SCIENTIST, PHYSICIAN WHO IS ALSO AN INCREDIBLY ACCOMPLISHED--I DON'T WANT TO USE THE WORD ADMINISTRATOR BUT AT ANY RATE, WE MARK WHAT IT IS, SHE'S THE CHIEF SCIENTIFIC OFFICER'VE NIMBUS THERAPEUTICS WHICH IS WHICH IS A SMALL BIOTECH COMPANY IN BOSTON AND IT'S A AND SHE HAS DEVELOPED A TOPIC AS OF TODAY. AND OUR FIRST SPEAKER IS YARON ROTMAN, AND HE IS CHIEF OF THE LIVER METABOLISM BRANCH AT AT [INDISCERNIBLE] AT THE RAVINE MEDICAL CENTER IN P A TIQUA, AND CAME HERE FOR A HEPATOLOGY FELLOWSHIP AND SINCE AUGUST OF 2009 HAS BEEN A FACULTY MEMBER, A TENURED TRACK INVESTIGATOR IN THE BEGINNING HE FOCUSED A LOT ON HEPATITIS C, THAT'S BECOMING A BIT PASS A AND THAT'S SHIFTED BACK TO THE PATHOPHYSIOLOGY OF FATTY LIVER DISEASE AND HE'S INVOLVED IN CLINICAL TRIALS, HE'S INVOLVED IN COLLABORATIVE STUDIES OF VARIOUS KINDS AND IF I CAN GET THIS THING TO WORK--OKAY. SO HERE'S SOME OF THE QUICK THINGS THAT WENT THROUGH MY HEAD WHEN WE PUT THIS PROGRAM TOGETHER AND YOU PROBABLY HAVE YOUR OWN. BUT THIS WILL GIVE US A LITTLE FOCUS. LET SO PRIOR TO 1990 NO 1 TALKED ABOUT NONALCOHOLIC FATTY LIVER DISEASE. AND IN FACT, IF WE WERE ON A PATIENT WITH A BIOPSY, THERE WAS FAT TRIGLYCERIDES SITTING THERE, YOU WOULD INTERROGATE THE HELL OUT OF THE PATIENT ACCUSING THEM OF ALCOHOLISM AND THEN YOU'RE A CLOSET ALCOHOLIC BECAUSE ALL WE KNEW WAS ALCOHOLIC LIVER DISEASE. NOW THERE WERE A FEW RARE METABOLIC DISORDERS, HEMA CHROMEATOSEIS, OTHER THINGS, DIABETES, WHERE THERE WAS SOME LIPID BUT THAT WAS PRETTY RARE STUFF. IF YOU HAD FAT IN LIVER YOU WERE AN ALCOHOLIC SO YOU BETTER TELL ME ABOUT BUT I DON'T DOCTOR, I DON'T DRINK! BUT WHAT HAPPENED? IT'S 1 OF THE BIG MYSTERIES. I MEAN THE CURRENT VOGUE IS THAT THE DIET CHANGED, THE CULTURAL PATTERN CHANGED, MORE CALORIES AND MORE CARBOHYDRATE, MORE FAT PEOPLE, MORE DIABETES, MORE FATTY LIVER, AND MAYBE THAT IS IT. THAT MAY BE AN IMPORTANT CATALYST BUT AS YOU'LL HEAR, IT'S NOT THE ONLY STORY. SO THE INCOME THING IS IS NONALCOHOLIC FATTY LIVER DISEASE WHICH IS NOW EFFECTING MILLIONS OF PEOPLE ALL AROUND THE WORLD BUT PARTICULARLY IN COUNTRIES THAT HAVE HIGH CALORIC INTAKE AND MAYBE NOT SO MUCH EXERCISE, I DON'T KNOW, BUT YOU KNOW WHAT IS IT? IS IT A SYNDROME? THAT MEANS YOU GOT FAT IN THE LIVER BUT IT BE CAUSED BY MANY DIFFERENT CAUSES. OR IS IT A SPECIFIC DISEASE. IS IT A DEFECT IN XYZ CHAIN? WELL TO SOME PEOPLE THOSE ARE FACILITATING FACTORS BUT FOR A LOT OF PEOPLE THEY AREN'T. NOT EVERYBODY WAS FATTY LIVER DISEASE IS FAT OR RATHER SKINNER IN CERTAIN PARTS OF THE WORLD SO A LOT OF UPS AND DOWNS. NEXT, IS NONALCOHOLIC FATTY LIVER DISEASE SERIOUS? DOES IT MATTER? TO HAVE MORE FAT IN LIVER, WE DON'T KNOW THE FULL ANSWER TO NABUT WE DO KNOW THERE IS SOMETHING CALLED STEATO-HEPATITIS. WHICH IS AN INFLAMMATTORY FIB ROTTIC SIROTTIC CANCER SEQUENCE, NOW DOES NAFL PROGRESSION TO NASH? EPIDEMIOLOGICALLY IT DOES SOMEWHAT BUT WE DON'T KNOW. THAT'S IMPORTANT BECAUSE NASH IS A SERIOUS BUSINESS. LEADS TO TRANSPLANTATION LEADS TO DEATH. AND A LOT OF TIMES--WELL I SAID LED TO TRANSPLANTATION. SO IF NAFL IS PART OF THE ICEBERG THAT'S BELOW THE SURFACE OF THE WATER, AND NASH IS ON TOP, SHOULD EVERYBODY WITH NAFL BE TREATED WITH DRUGS IF YOU CAN DEVELOP DRUGS THAT TREAT FATTY LIVER. NOW WE'RE TALKING ABOUT HUNDREDS OF MILLIONS OF PEOPLE AND HUNDREDS AND MILLIONS OF DOLLARS WHICH IS A CATALYST IN THE SUDDEN BURST OF INTEREST IN NAFL AND NASH. I THINK 1 OF THE OTHER REASONS FOR THE SUDDEN BURST OF INTEREST IS BECAUSE HEPATOLOGYST HAVE NOW MORE OR LESS LICKED HEPATITIS C WHICH WAS THE BIG TOPIC. THIS IS THE NEXT BIG TOPIC. THIS IS TOUTED AS THE MAJOR LIVER DISEASE INCREASING. OKAY, SO HOW DO WE DIAGNOSE IT? IS THE LIVER BIOPSY GOOD, BAD, INDIFFERENT? ARE THERE MARKERS WHERE YOU CAN JUST TEST? ARE THERE NONINVASIVE WAYS? ANYWAY THAT'S THE BROAD SUBJECT OF TODAY AND YARON, YOU WILL ANSWER ALL THESE QUESTIONS. >> OKAY, WORKING? THANK YOU FOR THE INTRODUCTION, I FEEL LIKE I'M ON THE CNN PARTY DEBATE WHERE I WAS HIT WITH QUESTIONS I WASN'T PREPARED BUT BUT I WILL TRY TO ANSWER AT LEAST SOME OF THEM AND THE REST I WILL MAKE UP LIKE THE POLITICIANS DO. [LAUGHTER] SO I SO JUST SOME DISCLOSURES, I DON'T MAKE ANY MONEY OUT OF THIS THE DISEASE. EVERYTHING I WILL SAY THERAPEUTICALLY IS OFFLABEL BECAUSE THERE IS NO APPROVED THERAPY FOR FATTY LIVER DISEASE AND JUST AS WIN SAID BE WARE OF THE IDES OF MARCH BUT WHAT'S LIVER KNOWN BECAUSE THE SOOTHSAYER WHO WARNED JULIUS SEASON 2006 YEARS AGO BASED HIS RECOMMENDATION ON READ NOTHING THE LIVER OF SLAUGHTERS ANIMALS. SO IF YOUR LIVER SAID SOMETHING TO YOU, YOU BETTER LISTEN TO IT. I DIDN'T BRING THE LIVE PATIENT BUT I DID BRING A CASE, A DEMONSTRATIVE CASE SO JOHN DOE IS A 52 YEARLY HISPANIC I SEE IN MY CLINIC. VERY--HE WAS INDENTALLY IF YOU UNDERSTAND TO HAVE ELEVATED ENZYMES IN THE LIVER, ALT WAS FOUND, HE WAS MILD FATIGUE, QUESTION FOUND JUST UNDER PHYSICAL, PHYSICAL ELIM NATION IS INAUDIBLE FOR BEING OBESE, BMI OR BODY MASS INDEX IS 37, THE NORMAL RANGE IS 19-25 PER THE BMI 37, I WOULD HAVE TO GAIN SOMETHING LIKE 45 KILOS OR A HUNDRED POUNDS FOR MY HEIGHT SO THAT GIVES AWE A RANGE OF WHERE IN TERMS OF ON, BEESITY. THESE ARE OTHER DISORDERS ASSOCIATED WITH OBESITY LIKE HYPERTENSION OBSTRUCTIVE THROUGH THE SLEEP APNEA AND WE ROOT OUT THE OTHER RISK FACTORS FOR LIVER DISEASE AND WE RULE OUT THE ULTRASOUND, THE ULTRASOUND SHOWS FATTY LIVERS, THAT'S WHAT HE HAS, HE HAS NONALCOHOLIC FATTY LIVER DISEASE. THE SUBJECT OF OUR TALK TODAY. I DID SOMETHING WRONG. I DID SOMETHING RIGHT. SO THIS IS NOT HIM OF COURSE, THE LATE JULIUS CAESAR, THIS IS WHAT I'M GOING TO TALK ABOUT TODAY, I WILL TALK ABOUT CLINICAL FEATURES OF THE DISEASE, NOT ALL OF THEM. I WILL HEIGHT LIGHT SOME ASPECT OF MECHANISM AND THEN--HIGHLIGHT SOME ASPECT OF MECHANISM AND THAT WILL DISCUSS TREATMENT OPTIONS NOW IN THE CLINICAL WORLD. BUT FIRST, THE NICE CONNECTION TO WHAT WIN SAID EARLIER, THIS IS THE FIRST DESCRIPTION OF THE LITERATURE. IT'S FROM 1980 FROM THE GREAT LUDWIG IN THE MAYO CLINIC, IT'S WORTH READ THANKSGIVING OUTLOUD, THE RECOGNITION OF NONALCOHOLIC STEATO-HEPATITIS WILL IMMEDIATE BENEFITS OF PATIENTS AND THEIR DOCTORS; THE AFFECTED PATIENTS WILL NO LONGER BE ACCUSED, DIRECTLY OR BY IMPLICATION OF LYING ABOUT THEIR ALCOHOL INTAKE AND PHYSICIANS WILL BE SPARED THE EMBARRASSMENT OR WORSE, THAT MAY RESULT FROM ENUING VERBAL EXCHANGES. IF YOU LOOK AT PUBMED, UNTIL MID1990S THERE WAS 1 TO 2 PAPERS A YEAR ABOUT THE TOPIC. CURRENTLY, WE'RE PLATEAUED AT 1000 PAPERS A YEAR PUBLISHED JUST ON THAT TERM. SO OBVIOUSLY THERE'S AN EXPLOSION OF INTEREST AND EXPLOSION OF KNOWLEDGE, MAYBE AN EXPLOSION OF THE DISEASE ITSELF. WILL SO LET'S DEFINE IT, WHAT IS NONWHALE WHOLIC FATTY LIVER DISEASE, IT'S EXCESS FAT IN THE LIVER, I WILL SAY TRIGLYCERIDES AND I WILL USE THIS TERM INTERCHANGEABLILY, WE HAVE DATA FROM 2 DIFFERENT STUDIES, 1 OF THEM IS AN OLD STUDY AT THE NIH IN 1970 WHERE JUST AUTOPSYS OF NORMAL PEOPLE, IF YOU LOOK AT DATA AND IT'S NOT IN THE PAPER, THERE'S ABOUT 50-MILLIGRAMS PER GRAM OR 5% AND THEN WE HAVE A POPULATION BASED STUDY FROM DALLAS USING MRI MEASUREMENT AND THEY REACH THE SAME NUMBER, SO ABOUT 5%. SO 5 PERCENT OR SO IS CONSIDERED THE NORMAL UPPER LIMIT OF TRIGLYCERIDES IN THE LIVER. WE CAN BREAK THE DISEASE IN 2 DIFFERENT FORMS. ONE IS JUST STEATOSEIS OR [INDISCERNIBLE] JUST IN THE LIVER AND NOTHINGALCY THE OTHER IS NONALCOHOLIC STEATO-HEPATITIS AND THIS IS A PROGRESSIVE DISEASE THAT EVENTUALLY CAN LEAD TO CIRRHOSIS WITH ALL OF THE COMPLICATIONS AND RELATED TO LIVER RELATED DEATH AND LIVER RELATED SUFFERING. HOW COMMON IS IT? IT DEPENDS HOW YOU LOOK AND WHAT YOU USE AND DEPEND WHEN IS YOU'RE ASKING THE QUESTION, IF YOU LOOK SAT DAILY BASIS FROM THE LATE 80S, EARLY 90S, THIS IS BASED ON THE NHANES WHICH IS A U.S. EPIDEMIOLOGICAL AND NUTRITIONAL SURVEY. SO IF YOU LOOK AT THAT POPULATION BY ELEVATED LIVER ENZYMES IS THE MARKER, ABOUT 5% HAVE FATTY LIVER. WHEN YOU LOOK AT EXACTLY THE SAME POPULATION WITH IMAGING, 20% OR NEARLY 20% HAD FATTY LIVER AND THAT'S A MORE ACCURATE WAY TO LOOK AT IT AND IF YOU GO BACK, DECADE AND A HALF OR 2 DAKADES LATER THIS IS POPULATION STUDIES FROM TEXAS AND YOU FEED THE NUMBERS RANKED TWEEP 30-45% OF THE U.S. POPULATION. IT'S NOW THE MOST COMMON CAUSE FOR LIVER TEST, CAUSE FOR--IF YOU DON'T HAVE ANY OTHER EXPLANATION FOR NORMAL LIVER SET, THIS IS THE CAUSE IN MOST CASES. IT WILL BECOME THE LEADING CAUSE FOR LIVER TRANSPLANT AND FOR LIVER RELATED MORTALITY. IF YOU THINK IT'S JUST THE U.S. AND IT'S JUST A PROBLEM OF THE WEST INVOLVED THIS IS A NICE GRAPH AGAIN ABOUT A DECADE AGO SHOWING THE ASSOCIATION BETWEEN OBESITY IN DIFFERENT COUNTRIES AND PREVALENCE EFFECTING LIVER IN DIFFERENT COUNTRIES AND THIS WAS JUST COMPRISED ON DIFFERENT PAPERS BUT YOU SEE, THIS IS HAPPENING EVERYWHERE, AND IT'S SEEN IN PEDIATRIC POPULATIONS AND KIDS ARE PRESENTED WITH CIRRHOSIS NOW SO THIS IS NOT TRIVIAL. WE THINK IT'S [INDISCERNIBLE], THIS IS WORK WE DID, WE ARE WORKING ON. WE LOOKED AT THE HEALTHY VOLUNTEERS FOR CLINICAL TRIALS AT THE NIH, IN ANYONE HERE MUST HAVE BEEN A PARTICIPANT IN AT LEAST 1 STUDY AND WE JUST PULLED ALMOST 3500 PATIENTS. THIS IS DONE WITH VARUN TAKYAR IN OUR GROUP. 56% OF THEM DID NOT HAVE NORMAL WEIGHT, 45% OF THEM DID NOT HAVE NORMAL LIVER ENZYMES AND WHEN YOU COMBINE THE 2, AS A VERY ROUGH MARKER, 30%. SO EVEN IF I'M WRONG BY DO YOU BELIEVE THE ESTIMATED--STILL A HUGE NUMBER OF PEOPLE HAVE FATTY LIVER AND THIS IS A LOT OF IMPLICATIONS, IF ANYONE IS RECRUITING THESE PATIENTS FOR EXAMPLE, FOR DRUG METABOLISM STUDIES OR OTHER THINGS, THIS MAY ACTUALLY HAVE A LOT OF FEEDBACK. SO OUR 2, WE ARE DEPENDENT ON LIVER BIOPSY, THIS IS JULIUS CAESAR UNDER GOING A LIVER BIOPSY OR NOT. THIS IS TELLING US WHAT'S GOING ON IN THE LIVER. LET ANDA WE LOOK AT SEVERAL AXIS THAT ARE NOT PERFECTLY CORRELATED WITH EACH OTHER. STOP GOING TO THIS SLIDE SO EVERYONE GETS--WE ARE LOOKING AT THE, AMOUNT OF FAT IF THE LIVER, AMOUNT OF INFLAMMATION AND INFLAMMATORY CELLS THAT INFILTRATE THE LIVER, CELLIAR INJURY AND THE OUTCOME OF ALL OF THIS WHICH IS THE FIBROSIS, THE POSITION OF COLLAGEN AND CAN YOU SEE AN EXAMPLE, THE TOPIC IS NORMAL LIVER. NORMAL BOTTOM PICTURE ON THE LEFT IS THE WHITE GLOBULES WHERE THE FAT USED TO BE AND WAS WASHED OUT BY FORMALDEHYDE. THERE'S A SPRINKLING OF INFLAMMATORY CELLS, CELLS THAT ARE BALOONS, STOLEN, THESE ARE FROM INJURY AND IF WE USE THESE BLUE STAIN FOR COLLAGEN, THE POSITION THAT CAN EVENT WHY ULTIMATELILY LEAD TO FIBROSIS, CIRRHOSIS PROBLEM AND SOMETHING THAT PLAGUED THE FIELD IS THAT WE CAN DO NOT HAVE ANY RELIABLE WAY TO DIFFERENTIATE NASH, THE PROGRESSIVE PROBLEMATIC DISEASE FROM JUST FAT IN THE LIVER. A LOT OF STUDIES ABOUT BIOMARKERS SIRROLOGY, IMAGING, NONE OF THEM ARE GOOD ENOUGH TO ALLOW FOR CLINICAL DECISION MAKING. GOING TO NATURALLY HISTORY, IS FATTY LIVER EVEN A PROBLEM? FIRST DOES IT PROGRESS OR DOES IT NOT? THIS IS A NICE STUDY THAT COMPARES PEOPLE TO 2 PEOPLE WITH PAIRED LIVER BIOPSY, THAT HAS MORE MAN 1 LIVER BIOPSY AND IT SHOWS THAT FATOT FIRST BIOPSY WITH NO INFLAMMATION, NO OTHER MARKERS OF INJURY, YOUR CHANCES OF PROGRESSING TOWARD LIVER DISEASE AND DEVELOPING CIRRHOSIS WERE NOT VERY HIGH. HOWEVER IF YOU HAD SOME DEGREE OF INJURY OR INFLAMMATION IN THE LIVER BIOPSY, YOU WERE LIKELY TO PROGRESS IN IT AT 12 YEARS, ALMOST MORE THAN 75 OR 80% OF THESE PEOPLE ALREADY PROGRESSED AND DEVELOPED ADVANCED FIBROSIS. SO THERE ARE DEFINITELY 2 POPULATIONS AND 1 WITH PROGRESSIVE DISEASE AND 1 WITHOUT. NOW THAT IS INCREASED MORTALITY. AND COMPARED TO THE POPULATION IN THE DARK LINE, THE DASH LINE SHOWED THAT PEOPLE WITH FATTY LIVER DISEASE AT THE BEGINNING ACTUALLY STOP AND BY MORE THAN THEIR AGE ADJUSTED COLLEAGUES OR OTHER PEOPLE. BUT WHEN YOU BREAK IT DOWN TO NASH AND NON-NASH OR HERE THEY BROKE IT DOWN BY FIBROSIS BUT IT DOESN'T REALLY MATTER, YOU SLEEP APNEA AND OBESITYY THAT THE NASH PATIENTS ARE DYING MORE. THAT THE OTHERS ARE VERY CLOSE TO THE GENERAL POPULATION AND THIS CAN BE BROKEN DOWN IN MORE DETAIL BUT OVERALL WE HAVE A PROGRESSIVE DISEASE THAT CAN KILL YOU. WHAT IS IL? THIS IS SOMETHING WE'RE DOING WITH OHAD ETZION, AND WE PROVED THAT ALMOST 11,000 PEOPLE THAT UNDER WENT CARDIAC PERFUSION SCAN, AND THEY SCANNED IMAGE THEIR HEART AND IT'S PROFUSION, AND FOLLOWING THEM FOR 5 YEARS AND LOOKING AT THOSE WHO HAVE ELEVATED AMC WITH NO CLEAR EXPLANATION, ABOUT 15% OR 14% AND WE'RE ASSUMING THE MAJORITY OF THESE ARE PATIENTS WITH FATTY LIVER. WHAT'S THE IMPACT ON MORTALITY? IT'S VERY INTERESTING. THEY HAVE AN INCREASED CARDIOVASCULAR DEATH, THEY HAVE HIGHER RISK OF CARDIO DEATH AND INFARCT, HEART ATTACK, AND INTERESTINGLY THIS CAN ONLY BE SHOWN IN THOSE THAT HAVE HAD A NORMAL SCAN. SO LET ME INTERPRET IT, SHOWING THE SIGNIFICANT HEART DISEASE, IT DOESN'T MATTER WHAT YOUR AALT IS, YOU WILL DIE OF HEART DISEASE BUT IF YOU THINK YOU'RE HEALTHY, YOU HAVE A SCAN THAT SHOWS YOUR HEART IS REASONABLY WELL, BUT YOU HAVE ELEVATED, ALT, YOU ARE AT RISK OF DYING FROM CARDIOVASCULAR DISEASE, SO YOU THINK YOU ARE MILD, YOU ARE PROGRESSED AND INDEED, IN OTHER STUDIES THIS IS DATA FROM THE SWEDISH CO HORDE, CARDIOVASCULAR DISEASE IS THE NUMBER 1 CAUSE OF MORTALITY FOR FATTY LIVER PATIENT, THE SAME AS IN THE REST OF THE POPULATION AND CANCER IS THE NUMBER 2, AT THE SAME AS THE OTHER PATIENT, THEY HAVE INCREASED MORTALITY BUT THEY DIE OF THE SAME CAUSES, THEY CAN DIE OF LIVER DISEASE. IT'S THE THIRD CAUSE IN THE GENERAL POPULATION, BUT IT'S ONLY--THEY ONLY 6% OF THEM WILL DIE OF LIVER DISEASE. SO, AS A HEPATITIS EATOLOGYST WHEN I TREAT NASH, I HAVE TO THINK ABOUT MY PATIENTS. --SORRY, I THOUGHT THIS WAS A GOOD 1. LET'S TALK ABOUT MECHANISM, I'D LIKE TO FOCUS ON 2 THINGS WE CAN SPEND 3 DAYS TALKING ON MECHANISM BUT I WANT TO TALK ABOUT THE FATE OF FAT, AND WHERE DOES IT COME FROM AND WHERE DOES IT GO IN THE LIVER AND THEN WE'LL TALK ABOUT SOME INJURY MECHANISM. SO FAT CAN COME TO THE LIVER IN THE FORM OF FATTY ACIDS FROM 3 MAIN SOURCES. THEY ARE COMING FROM THE MEAL AND THIS IS I VERY MINOR AND ALMOST NEGLIGIBLE. THEY CAN,A RIFE THROUGH THE LIVER IN THE FORM OF FREE FATTY ACID AND GENERATED AS DE NOVO LIB O GENESIS, WHAT CAN HAPPEN TO THESE? THEY CAN BE CONVERTED TO TRIGLYCERIDES AS AN VLDR LAND THEY CAN BE ALSO TO OXIDATION AND OTHER METABOLISM PATHWAYS. LET'S LOOK AT THIS 1 BY 1, SO THIS TISSUE, TO THE LIVER. SO FAT IN ESSENCE, IN FACT THE HOLDING COMPANY KIEWL IS AN ENERGY STORAGE MOLECULE SO WE HAVE ACCESS COLORYS WHEN WE'RE EATING WE CAN STORE ENERGY, WHEN WE'RE STARVING WE CAN USE THAT ENERGY, IT'S LIKE A CAPACITATOR IT KEEPS THE ENERGY SUPPLY, IT CAN KEEP IT IN TABLE LEVEL. SO FOR THAT REASON, WHEN WE'RE FEEDING WE DON'T NEED FAT TO BE RELEASED FROM THE TISSUE, WE HAVE CALORIES FROM THE FOOD. WHEN WE'RE FASTING WE NEED THE FAT TO BE RELEASED FROM THE TISSUE, SO INSULIN, THE WHOLE LEVEL OF SATIETY, AND NORMAL SUBJECTS IN BLACK, THE RELEASE OF THE FATTY ACIDS FROM THE TISSUES DECREASE 80% WHEN YOU GIVE THEM INSULIN. THIS IS THE NORMAL REACTION, ON THE OTHER HAND IF YOU LOOK AT PATIENTS WITH FATTY LIVER DISEASE, THIS IS ACTUALLY--IT'S DECREASED BUT NOT TO THE SAME DEGREE, SO WHAT WE SEE HERE. WE SEE ADISCIPLINARY POS TISSUE, IT IS NOT RELEASED THE WAY IT SHOULD, IT'S RELEASING MORE THAN GET TO THE LIVER. THIS A NICE MULTIPLE LABEL FROMI LESBETH'S GROUP THAT SHOW THAT A MAJORITY IN IT THE LIVER AND THE TRIGLYCERIDES IS COMING FROM THESE. FROM THE ADI POS TISSUE FROM THE MAIN SOURCE TO THE CELL ACCUMULATION. WHAT ABOUT THE OUTER PATHWAY FOR THE DEGLYCO GENESIS AND YOU WILL HEAR MORE ABOUT IT FROM MY COLLEAGUE, BUT IF WE JUST FOCUS AGAIN ON OTHER MULTILABEL STUDY, IT'S MARKEDLY INCREASED IN THIS PARTYS THAN WHAT YOU SEE IN OTHERS. WE HAVE DELIVERY TO THE LIVER AND PRODUCTION, CARBOHYDRATE PRECURSOR NTH THE LIVER. NOW MAKING A STEP BACK AND THINKING ABOUT INSULIN SIGNALING, AS I SAID INSULIN IS THE HORMONE OF ENERGY PRESENT, ACCESS. AND THE--NORMAL ACTION OF INSULINOT LIVER DOES MORE THAN 1 THING. IT TELLS THE LIVER, THERE'S NO NEED FOR ENDOGENOUS GLUCOSE PRODUCTION, DON'T RELEASE ENERGY, STORE ENERGY. IT ALSO TELLS THE LIVER, STORE THEM WITH TRIGLYCERIDES SO IF WE'RE TALKING ABOUT LIVER INSULIN RESISTANCE, WE SHOULD EXPECT THE DECREASING FAT ACCUMULATION AND AN INCREASE IN FAT ACCUMULATION AND 1 OF THE THEORIES. IT'S NOT UNIVERSALLY I THINK ACCEPTED BUT IT'S GAINING MORE GROUND IS THAT WHAT WE HAVE IS ACTUALLY SELECTIVE IPT GREATER SURVEYS LYNN RESISTANCE, THE PATHWAY THAT LEAVES THE CONTROLLED CARBOHYDRATE IS RESISTANT SO THE LIVER, DESPITE INDENT THE LIVER IS POURING LESS GLYCO GEN IS WORSENING TO THOSE FEEDBACK LOOPS, THE HYPER INSULIN ANEMIA BUT THAT FORMATION TOWARDS THE FORMATION IS INTACT SO THERE'S SO THIS IS DRIVING MORE AND MORE INFORMATION WITH THE LIPO GENESIS AND GENERATION OF TRIGLYCERIDES AND THIS WAS NICELY SHOWN IN A HUMAN STUDY WHICH LOOKS AT RARE PATIENTS OF NIH PATIENTS INCLUDED IN THIS STUDY AS WELL. WITH MUTATIONS IN SOME OF THE INSULIN SIGNALING PATHWAY. SO WHEN YOU LOOK AT PEOPLE WHO HAVE A MUTATION, THEY'RE COMPLETELY RESISTANT TO INSULIN. THERE ARE SOME BYPASSES BUT ESSENTIALLY THEY CAN RESPOND, AND THEY HAVE SEVERE DIABETES AND HUGE DOSES OF INSULIN, THEY NEVER DEVELOP THAT LIVER BECAUSE THEIR LIVER IS COMPLETELY RESISTANT. WHEN YOU LOOK AT PEOPLE WITH A MUTATION--LOOKING AT THE FACAS METABOLISM THE OTHER WAY, WHAT HAPPENS TO THESE FATTY ACIDS? ONE IS TO UTILIZE THEM FOR ENERGY AND THE TRUTH OF THE MATTER IS THAT THIS IS UNCLEAR, THIS SUGGESTS THERE IS AN INCREASE IN BETAOXIDATION WITH THE FATTY LIVER BUT IT'S NOT SUFFICIENT TO HANDLE THE EXCESS LOAD, SOME STUDIES SUGGEST THERE'S ACTUALLY A DECREASE, WE ARE ACTUALLY LOOKING AT THIS FROM ANOTHER PERSPECTIVE SITTING HERE, THEN WE'RE USING TO STUDY FOR THIS, WE'RE USING A FATTY ACID THAT'S LABELED WITH THE ISOTOPE KNOWN BY THE REACTIVE CARBON AND WE'RE USING THIS DEVICE THAT MEASURES IN THE BREDTH THE LABELED CO2 AND NO LABELED CO2 AND FOR NOW IT'S COMPARING FATTY LIVER PATIENTS WITH CONTROLS AND WE GET--THIS IS THE TYPICAL CURVE THAT WILL GET UP THERE DURING THE 6 HOURS YOU SEE AFTER THE PATIENT INGESTS THE MEAL THERE'S A SLOW APPEARANCE IN THE LABEL, AND THIS IS METABOLIZED OXIDIZED AND SOME OF IT GOES OUT TO AS KREBS CYCLE, O2. AND THE TIMING OF THE PEAK, THE LOOK AT THE PEAK OF THE CURVE AND THE AREA UNDER THE CURVE WHICH TELLS US HOW MUCH OF THE LABEL WE'RE GETTING, HOW MUCH DID HAY OXIDIZE AND WE SEE THAT THE TIMING OF THE PEAK DOES NOT DEFER BETWEEN HEALTHY CONTROLS AND SOME VERY NICE AND POST DOCS AND PATIENTS WITH FATTY LIVERS BUT ON THE OTHER HAND WHEN YOU LOOK AT THE AREA UNDER THE CURVE AND I THINK WE HAVE LIKE THEN IS 4 IN THE GROUP AND IT'S ALL VERY SIGNIFICANT, IT DOUBLES SO, THE PATIENTS WITH FATTY LIVER DISEASE ACTUALLY METABOLIZE ABOUT HALF AS MUCH AS THEIR HEALTHY CONTROLS IN TERMS OF PHARMACY. REMEMBER THIS IS NOT THE LIVER TEST, THIS IS A WHOLE BODY SO OTHER ORGANS THAT PLAY A ROLL, BUT SOMETHING THAT'S GOOD TO DO, IT'S HAVE INTERESTING. BUT IN GENERAL TO SUMMARIZE THIS PART THIS EFFECT THE LIVER BECAUSE THE ADI POS LIVER--FLUICOSE WHICH IS DRIVING THAT AS WELL BECAUSE YOU HAVE MORE PRODUCTS TO METABOLIZE. WE'RE NOT SURE IF THERE'S AN INCREASE OR DECREASE IN BETA OXIDATION BUT WHATEVER IT IS, IT'S NOT SUFFICIENT TO HANDLE THE LOAD AND MAY CAUSE TOXICITY BECAUSE OF INCOMPLETE OXIDATION AND THERE IS A AN INCREASE THAT I DIDN'T SHOW HERE BUT IT'S NOT ENOUGH TO COMPENSATE. SO EVENTUALLY WHAT WILL HAPPEN IS THAT WE ACCUMULATE THE FATTY ACIDS AND THEY'RE CONVERTED TO TRIGLYCERIDES. SO THAT'S OKAY, THAT'S ABOUT FATTY LIVER BUT WHY SHOULD WE HAVE THE HEPATITIS, WHY DO WE DEVELOP DAMAGE FROM THAT? SO INITIALLY AND THIS IS WRONG, SHY PUT AN X ON THIS, INITIALLY THE MODEL WAS A 2 HIT MODEL. YOU HAVE INSULIN RESISTANCE, ACCUMULATION OF FAT IN THE LIVER, IT CAUSES THE LIVER TO BE MORE INSULIN RESISTANT AND THEN COMES THE SECOND HIT AND THIS COULD BE CYTOKINES OR REACTIVE OXYGEN SPECIES OR LPS, OR WHATEVER THE POPULAR TOPIC OF THE YEAR. AND THAT CAUSES THE DAMAGE. SO THERE'S PIECES OF INFORMATION THAT CONTRADICT THIS AND SUGGEST THIS IS NOT THE CASE. FIRST TRIGLYCERIDES ARE NOT BAD FOR YOUR LIVER, THIS IS A CLASSIC EXAMPLE FROM THE LAB, THEY HAVE BLOCKED THE KEY ENZYME THAT IS THE [INDISCERNIBLE], THIS IS THE KEY ENZYME IN CONVERTING FREE FATTY ACIDS WITH GLYCEROL TO TRIGLYCERIDE. SO THIS IS RESPONSIBLE FOR GENERATING FAT FOR PREFATTY ACID. YOU KNOCK IT DOWN AND IT PRODUCES THE FATTY ACID THAT PRODUCES THE LIVER DISEASE. SO THESE ARE CONTROL ANIMALS. THESE ARE ANIMALS THAT THEY DIET INDUCED THE LIVER AND THEY HAVE AN INCREASE OF LIVER ENZYMES AND WHEN YOU KNOCK DOWN THESE ANIMAL'S ABILITY TO GENERATE TRIGLYCERIDES YOU DON'T GET FATTY LIVER BECAUSE THEY CAN'T. THEY CAN'T MAKE THE TRIGLYCERIDE. WHAT YOU DO GET IS TREMENDOUS AMOUNT OF DAMAGE, SO THE FACAS IS NOT THE CAUSE OF DAMAGE. IT'S PROTECTED. IT MAY BE A WAY TO SHUNT OTHER TOXIC THINGS INTO A MOLECULE THAT'S RELATIVELY INERT. DO THE TRIGLYCERIDES THEMSELVES DRIVE THE INSULIN IN THE LIVER? IT'S UNCLEAR BUT THERE'SA DATA THAT SUGGESTS THAT I DON'T AND WHAT THEY DID WAS ELEGANTLY, THEY USE PEOPLE WITH A GENETIC DEFECT, PEOPLE WITH FAMILIAR HYPER PROTEIN, THEY CANNOT OR THEY HAVE A DEFECTIVE SECRETION OF THE TRIGLYCERIDES FROM THE LIVER. SO THEY ACCUMULATE NOT BECAUSE OF THE CLASSIC FATTY LIVER BUT BECAUSE THEY CAN'T THROW THEM OUT. AND THEY ACTUALLY DO NOT HAVE SIGNIFICANT INSULIN RESISTANCE AND THEY'RE COMPARED TO PEOPLE WITH THE SAME WEIGHT, EVEN IF THEY'RE OVERWEIGHT BUT THEY DON'T HAVE INSULIN RESISTANCE IN THE LIVER SIMILAR TO PEOPLE WITH FATTY LIVER DISEASE, SO THESE DON'T SEEM TO BE CURIOUS AND THEY DON'T SEEM TO PROMOTE INSULIN RESISTANCE AND FINALLY, CLINICALLY, THE CLINICIANS HERE KNOW THAT MOST OF OUR PATIENTS WITH BAD HEPATITIS DON'T HAVE A LOT OF FAT IN THEIR LIVER. THERE SEEMS TO BE DISASSOCIATION BETWEEN THE 2 PHENOMENA. THE SO THEN WHAT DOES CAUSE THE PROBLEM AND AGAIN THIS WILL BE DISCUSSED FURTHER LATER BUT THE CONCEPT WE THINK ABOUT NOW IS OF LIPO TOXICITY. IF IT'S ACTUALLY METABOLITES EITHER THE FATTY ACIDS THEMSELVES OR METABOLITES LIKE THERMOGENESISIDE OR DISCIPLINARY GLYCEROL OR OR OTHER DERIVATIVE ARE ACCUMULATING AND CAUSING THE DAMAGE. AND INTERESTING CONCEPT RELATED TO BETAOXIDATION IS WHAT WE CAN MAY BE HAVE AN OVERLOAD OF THE MIGHT O CONDHIERAL CAPACITY. SO THEY CAN'T HANDLE THE LOAD AND THEN YOU GET PARTIALOXIGATION AND REACTIVE SPECIES WHICH DRIVES THROUGH OXIDATIVE STRESS, ER STRESS AND A LOT OF BUZZ WARDS BUT ESSENTIALLY THESE ARE ALL MEDIATORS OF DAMAGE. THERE ARE OTHER FACTORS LIKE CHOLESTEROL IT PLAYS A FACTOR IN THE DISEASE BUT WE TEND TO IGNORE IT. WE HAVE SOME MICRO BIOME THERE THAT SUGGEST THAT THEY PLAY A ROLE AND JUST 1 WORD ABOUT GENETICS, THEY'RE PROBABLY NOT AS STRONG AS WE WOULD LIKE THEM TO BE, THIS IS PRETTY GOOD BECAUSE I WROTE IT SO I MIGHT AS WELL PUT THE GRAPH HERE BUT 1 OF THE STRONGEST JEERPS IS THE PNP, THE ADISCIPLINARY POSE NUCLEOTIDES TRI END AND OTHER PEOPLE SHOW THAT MUSEUMITATION IN IT IS HIGHLY ASSOCIATED WITH THE DEGREE OF INJURY AND THE DEGREE OF FAT IN THESE PATIENTS AND IT'S INTERESTING THAT THE INJURY IS INDEPENDENT OF THE AMOUNT SUGGESTING THERE'S DISCREPANCY. IRRESPECTIVE OF HOW MUCH YOU HAVE IN YOUR LIVER, YOU WILL GET WORSE INJURY IF YOU HAVE THE RISK ALLELE. THIS IS OFF THE VARIANTS IN THE POPULATION, SO MOST OF IT IS PROBABLY NOT GENETIC, ALTHOUGH THERE ISN'T--SERIOUSLY THAT WE HAVEN'T BEEN ABLE TO ANSWER YET AND THIS IS THE RACIAL DIFFERENCE. HISPANICS ARE VERY PRONE TO FATTY LIVER DISEASE--AND WE HAVEN'T FOUND A GOOD EXPLANATION FOR IT. I CLICKED TOO MUCH AND JUST TALKING ABOUT--WE WILL FINISH WITH SOME DATA ON WHAT WHAT'S AVAILABLE NOW FOR SOME TREATMENT. SO I'LL COVER A FEW STRATEGIES AND TALK ABOUT INSULIN PATHWAYS AND BILE ACID AND ANTIOXIDANTS. I FOUND PSYCHE A BROKEN RECORD BUT THAT'S THE MAIN STAY OF TREATMENT LIKE ALL THE OTHER COMPLEMENTS OF METABOLIC SYNDROME, DIET, PHYSICAL ACTIVITY, IT WILL HELP WITH HYPERTENSION, BARIATRIC, ACHIEVES HISTOLOGICAL--CAN YOU GET THE LIVER TO LOOK BETTER. THIS IS DATA WE COLLECT FROM BASICALLY THIS IS A PRELUDE TO ANOTHER STUDY BUT WHERE WE HAVE 12 WEEKS OF LIFE AND THEY COME IN EVERY 2 WEEKS TO MEET THE NUTRITIONIST AND WE ASK THEM, WORK MORE AND WRITE DOWN. WE DON'T PUT THEM ON A TREADMILL, DON'T GIVE THEM THE FOOD OR ANYTHING LIKE THAT AND YOU CAN CLEARICALLY SEE THAT AS THE BMI DECREASES AFTER 12 WEEKS SO DOES THE LIVER FAT AND SO DO THEIR LIVER ENZYMES. AND IT'S VERY CONVINCING. WE REACH UP TO 12 WEEKS. A THIRD OF THEM HAVE NORMAL AMOUNT OF FAT IN THE LIVER, A THIRD OF THEM HAVE NORMAL LEVEL OF [INDISCERNIBLE], CRITERIA AND ACTUALLY ABOUT 15-20% OF THEM ON THE LIVER BIOPSY DON'T HAVE THESE, PEOPLE WE KNOW HAVE THE FATTY LIVERS AFTER 12 WEEKS HAVE NEAR NORMAL OR NORMAL LIVER BIOPSY, WHAT'S THE PROBLEM? IT'S SUSTAINABLE, OTHER DISEASES THIS CANNOT BE KEPT ACTUAL OF--SERIOUSLY WE DO IF IT FOR 12 WEEKS AND WE SEE THEM EVERY 8 WEEKS IN WITH A NUTRITIONIST AND REGAIN THE WEIGHT. THIS IS WEIGHT AND WEIGHT CONTINUES TO GO UP, EVEN THOUGH THEY'RE IN A CLINICAL TRIAL AND THEY SEE A NUTRITIONIST AND THIS HAS BEEN SHOWN IN MULTIPLE STUDIES, THIS IS VERY DIFFICULT TO SUSTAIN. SO THEN WE LOOK AT MEDSICATION TO HELP US. AND I THINK THE FIRST AND PROBABLY THE MOST SUCCESSFUL PATH SO FAR AS BEEN TO LOOK AT INSULIN DESENSITIZERS MAINLY BECAUSE THEY'RE APPROVED FOR DIABETES AND--LET'S GO ANOTHER DRUG IS IT A LOT OF THE PATHWAY, THIS IS NOT THE TOPIC BUT NUCLEOTIDES CLEAR RECEPTORS THAT REGULATE A LOT OF THE HAD--THERE ARE 3, ALPHA GAMMA AND DELTA AND--THOSE ARE BY THE LIGAND, BY TISSUE EXPRESSION AND THE RESULT IS THAT THE ALPHA IS MAINLY A FASTING SIGNAL AND MAYBE A FASTING SIGNAL DRIVING FATTY ACID OXIDATION AND WHERE GAM SAN FRANCISCO WORKING TO IMPROVE INSULIN SENSITIVITY BUT ALSO IN THE LIVER AND DELTA IS RESPONSIBLE FOR OTHER THINGS BUT INCLUDING PERIPHERAL INSULIN AND SENSITIVITY. I THINK THE MAIN MEDICATION FOR THIS GROUP THAT'S WORTH MENTIONING, IT'S CLINICALLY USED FOR DIABETES. LET IT'S A GAMMA AGONIST, IT WAS STUDIED IN MULTIPLE STUDIES FOR FATTY LIVER DISEASE, THIS IS AN EXAMPLE FROM THE TRIAL WHICH NIDDK FUNDED. IF YOU LOOK AT THE PLURIBU LINE COMPARING TO PLACEBO THIS WAS FOR 2 YEARS AND YOU SEE THAT THE LIVER ENZYME DECREASED NICELY ABOUT 35 UNITS OF A. L. T. AND THEY IMPROVE SENSITIVITY. HOWEVER THEY GAINED ABOUT 5 KILOGRAMS OF WEIGHT AND THAT'S A KNOWN EFFECT OF THE [INDISCERNIBLE] GAMMA AGONIST. THE META-ANALYSIS AND THE BOTTOM LINE IS PEOPLE ARE GAMMA AGONISTS WORK FOR FATTY LIVER. THEY IMPROVE THEY GAIN WHICH I DON'T LIKE AND THERE ARE SAFETY CONCERNS ABOUT PROBABLY ARE NOT THAT CONCERNING AND AGAIN PEOPLE DON'T LIKE TAKING THEM AND YOU ARE A MEMBER OF THIS CLASS, THAT WAS PUBLISHED ABOUT A PHASE 2 STUDY, THIS IS THE DUAL ACANIST, SO ON THE 2 PATHWAYS AT ONCE AND SHOWN PROMISING DATA FROM THE STUDIES AND THIS WAS 200 PATIENTS RANDOMIZED AND PLACEBO AND THIS IS AMBITIOUS AND THIS WAS COMPLETE HISTOLOGICAL RESOLUTION OF NASH AND THEY FAILED THE AMBITIOUS END POINT. AND THEY TRY TO JUSTIFY BY SAY THANKSGIVING IS PATIENTS WITH SEVERE DISEASE AND THEY INCLUDED PATIENTS WITH THE DISEASE, LET'S SAY THIS WAY ABOUT IF YOU LOOK AT RESPONSE CRITERIA, USING THE STUDY, THE VIA MIN E, THE STUDY THAT'S USED THERE'S THE SAME NUMBERS 48 PERCENT RESPONDENT VERSES 21% IN PLACEBO. LOOKS AT REALLY ABOUT THE SAME. AND THIS THE GP 1 AGANIST OR GLP1 MIMIC THAT'S A BETTER TERM TAR IT, THIS IS GUT DERIVED HORMONE THAT IS SECRETED FROM THE INTESTINE WHEN WE EAT. EVEN BEFORE THE FOOD GETS THERE AND IT IMPROVING TO SENSITIVITY BOTH BY ACTIONOT PANCREAS AND DECREASED GLUCCA GONE AND IT HAS ACTIVITYOT PERIPHERY, MAINLY LIVER AND DECREASES APPETITE AS WELL FOR ACTIONOT SEBTERAL NERVOUS SYSTEM, THERE'S BEEN SOME RETROSPECTIVE ANALYSIS AND PEOPLE HAVE ANALYZED IT SO OTHER MEDICATIONS SO THE SAME CLASS AND A LOT OF THEM SHOW BENEFIT IN DIABETIC PATIENT AND YOU TAKE THE PATIENTS AND YOU LOOK AT THOSE FOR THE ELEVATED LIVER ENZYMES AND IN THE STUDY, OH, IT WENT DOWN, THAT'S NICE. BUT THIS IS ACTUALLY THE ONLY REAL STUDY IT WAS JUST PUBLISHED A FEW WEEKS AGO IN THE LANSID, THEY HAD 40% SOLUTION OF NASH, WE ARE REPEATING OURSELVES AND THIS WAS SIGNIFICANTLY BETTER THAN PLACEBO WHICH IS SURPRISING SUCCESS FOR A SMALL STUDY. AND THE LIVER ENZYME WAS NICE, A NUMBER THAT SOUNDS FAMILIAR WITH PREVIOUS GRAFFS AND THEY LOST WEIGHT AND IT'S NOT CLEAR WHETHER THE BENEFIT IS INDEPENDENT OF THE WEIGHT LOSS. THEY DON'T HAVE A LARGE ENOUGH NUMBER TO SAY WHETHER THIS IS JUST A SIDE BENEFIT OF LOSING WEIGHT IN WHICH CASE, YOU MAY HAVE OTHER WAYS TO TREAT IT OVER THIS, OR IS THIS DIRECTLY RELATED TO [INDISCERNIBLE]. BUT THIS IS SOMETHING THAT WE'LL HEAR ABOUT MORE IN THESE STUDIES. FINALLY I WANT TO TALK ABOUT THE PATHWAY I HAVEN'T MENTIONED BEFORE, SO MEDICAL SCHOOL OR BIOLOGY 101 LEARN THAT THESE ARE IS SECRETED FROM THE LIVER AND THE ROLE IS TO ALLOW FOR A--BITS SORPTION OF THE MEAL. THEY HAVE WATER INSOLUBLE FAT TO BECOME INSOLUBLE AND THE MAJORITY IS TO REABSORBED AT THE END OF THE SMALL BOWEL AND GET RECIRCULATED SO MOST OF THE BILE AX SID GETS BACK TO THE LIVER AND THEREY--ACID GETS BACK TO THE LIVER AND THERE'S A WHOLE INTERACTION PATHWAY WITH THE GUT BACTERIA. THE THERE IS AN INTERESTING NUCLEAR RECEPTOR CALLED FXR AND SOME OF YOU WERE PRESENT IN THE VISITING PROFESSORS TALK LAST WEEK THAT WAS THE TOPIC OF A LOT OF DISCUSSION AND ETHICS ARE AN EXTRA CELLULAR; AND THEY ARE THE LIGAND AND ESPECIALLY IN THE LIVER WHEN IT'S ACTIVATED BY BILE ASSAY, IT WILL DOWN SUBSCRIPTIONALLY REGULATE IN SIP 7 AC1 OF THE INFORMATION SO IF YOU HAVE BILA,A SID, YOU DON'T MAKE MORE, YOU DOWN REGULATE THAT PATHWAY AND IT WILL ALSO UPREGULATE THE TRANSPORTERS THAT SECRETE BILE ACID OUT OF THE LIVER. SO IN A WAY, SO THE EXPLANATION, THIS IS SOMETHING THAT CONTROLS OR STABILIZES BILE THAT STABILIZES INTRACELLULAR BILE ACID LEVELS. THESE ARE ALSO IN THE [INDISCERNIBLE], WHERE IT'S ABSORBED AND ACTUALLY BOTH OF THOSE ON THE TRANSPORTERS END ON THE HORMONE,OT GUT [INDISCERNIBLE] FGF19 SO THEN CAN ASK DIRECTLY ON THE LIVER AND HAVE AN INSULIN LIKE EFFECT. HOWEVER IT WAS NOTED THAT THE ACTIVATION DOES A LOT MORE, AND HAS A STRONG METABOLIC ROLE AND THE METABOLISM ACTIVATION AND INSULIN AND DECREASES LIPO GENESIS AND FATTY ACID AND OXIDATION AND LOW AND BEHOLD A COMPANY ACTUALLY CAME UP AND MADE ACID WHICH A MODIFIED SYNTHETIC, AND--THE CRN NETWORK FOR THE STUDY WENT AHEAD AND DID THE TRIAL WITH THIS MEDICATION 72 WEEKS DOUBLE BLIND PLACEBO CONTROLS, AND THE SUBJEBTS SOME OF THE STUDIES ARE THE SAME, IT'S VERY EASY. AND THE RESULT, YES, 45% VERSES 21%, EXACTLY THE SAME NUMBERS: LIVER ENZYMES DECREASE BY 30 OR 40, EXACTLY THE SAME NUMBERS VERY FAVORABLE PROFILE FOR THE ENZYMATIC RESPONSE BUT ALSO THIS IS THE FIRST IMPROVEMENT TO SHOW SOME IMPROVEMENT AND IN FIBROSIS WHICH IS SOMETHING WE LIKE BUT I DON'T KNOW THAT THE BETA IS THAT CONVINCING THAT IT'S THAT STRONG BUT THIS IS SURPRISINGLY WORSE THAN INSULIN RESISTANCE AND THIS WORSE THAN THE CHOLESTEROL PROFILE AND ABOUT A QUARTER OF THE PATIENTSATE SO MUCH THAT SOME OF THEM HAD TO STOP AND WHEN YOU LOOK AT THE RESOLUTION, IT'S NOT IMPROVEMENT, IT'S ONLY 20%. SO THIS IS ACTUALLY PART OF THE PHASE 3 STUDY, THIS IS PART OF THE FATTY LIVER DISEASE, THIS WILL CAPTURE THE GOOD TREATMENT I'M NOT CONVINCED. FINALLY I WANT TO TALK ABOUT ANTIOXIDANTS. SO WE TALK ABOUT THE ACCUMULATION OF [INDISCERNIBLE] AND METABOLITE BUT ANOTHER APPROACH CAN SAY, YOU KNOW WHAT? I CAN'T DEAL WITH THE FAT YOU HAVE FAT SAY WITH IT, YOU HAVE TAXIC METABOLITES, IT'S OXIDATIVE SPECIES, LET'S JUST SAY WE'LL JUST TAKE CARE OF THESE AND THAT CAN SOLVE THE PROBLEM. SO THE BEST PART OF THIS, WAS VITAMIN E AND IT'S WIDELY USE INTERESTED WIDELY AVAILABLE AND THE SAME STUDY THAT THEY SHOWED YOU EARLIER ACTUALLY HAD A VITAMIN E AND THEY USE IT FOR THOSE VITAMIN PEOPLE DOWN THAT GET RID OF THEM AND SURPRISINGLY, 43% HAD HISTOLOGICAL RESPONSE VERSES 20% IN THE PLACEBO ARM, IT WOULD BE BETTER THAN [INDISCERNIBLE]. IF YOU'VE SEEN THIS BEFORE, YOU SEE THE [INDISCERNIBLE] MAGIC NUMBER. IT'S NOT IMPACT INSULIN RESISTANT BECAUSE IT'S NOT SURPRISED TO. IT'S SUPPOSED TO BE WAY DOWN STREAM OF THE PET, SO IT LOOKS REALLY GOOD. ONE INTERESTING THING IN THE PEDIATRIC STUDY MORE AT THE SAME TIME THIS IS ASSOCIATED WITH A DECRETES IN THE AMOUNT OF LIVER FAT AND IF YOU THINK ABOUT IT, IT DOESN'T MAKE SENSE, IT WASN'T SUPPOSED TO. AM THIS WAS SUPPOSED TO BE DOWN STREAM, THE INJURY OF THE LIVER, IT'S EFFECTED LIVER WHY DOES IT DO IT? NO GOODS ANSWER BUT HOPEFULLY IN A FEW YEARS I WILL BE ABLE TO TELL YOU. BUT THIS IS CLINICAL DAT FROM THAT STUDY WHICH IS THE STUDY IS GOING TO LOOK AT MOLECULAR MECHANISMS BUT JUST SOME OF THE CLINICAL RESULTS THAT WE HAVE AND WE REPLICATE IT WITH VITAMIN E IN PATIENTS WITH FATTY LIVER DISEASE, WE NORMALIZE IT DECREASE THE NORMALIZE IN 20 PERCENT AND WE HAVE LIVER BIOPSY, AND VERY EARLY WITHIN A MONTH OF TREATMENT, 60% OF THEM SHOW HISTOLOGICAL IMPROVEMENT SO WE CAN ARGUE WHAT THE MECHANISMS ARE. WE'RE LOOKING AT DIFFERENT DOSES AND IT LOOKS AS IF IT'S A TREND BUT IT'S TOO EARLY TO SAY ANYTHING ABOUT SIGNIFICANCE AND JUST MORE OR LESS BY COMPARING THE DIFFERENT OPTIONS WE HAVE. SO, I'VE SPOKEN ABOUT ALL OF THESE BUT THE BEST TREATMENT IS LIFESTYLE BUT AGAIN THE IS SHE WHETHER SUSTAINABLE RESOLUTION OF NASH LOWER NUMBERS AS WELL AND I BEING WE CAN TALK ABOUT THE CHALLENGES WE HAVEN'T STUDIED FATTY LIVER DISEASE, LIVER BIOPSIES BECAUSE WE DON'T HAVE GOOD ENOUGH MARKERS BECAUSE WE'RE TREATING THESE WHICH IS NOT NECESSARILY WE GOT THE LIVER TO LOOK BETTER BUT THAT DOES MEAN THEY DIE LESS OF CARDIOVASCULAR [INDISCERNIBLE] WE DON'T KNOW THAT. IT WILL TAKE A LONG TIME UNTIL WE KNOW. WE DON'T HAVE STUDIES THAT TREAT PATIENTS FOR CONTINUOUSLY FOR 20 YEARS OR SO. WE DESCROANT DATA FOR PHASE 3 TRIALS. WE ONLY HAVE 1 STUDY THAT STARTED AND FINALLY HUMANS ARE DIFFERENT THAN MICE, A LOT OF THINGS THEY'RE PROMISING IN ANIMALS THEY HAVE FAILED OR NOT BEEN AS SUCCESSFUL IN HUMANS. WE'LL FINISH WITH JOHN, THE PATIENT I TOLD YOU ABOUT BEFORE. WE BIOPSIES HE WENT TO THE STUDY, THE BLUE LINE IS THE WEIGHT, HE LOST WEIGHT NICELY. HIS LIVER ENZYME I IMPROVED. HIS LIVER FAT NORMALIZED WE PUT HIM ON VITAMIN E. HE IMPROVED SOME MORE WITHIN THE VITAMIN E, IT HAD NO FAT IN HIS LIVER, BUT HE HAD 0.06%, NOTHING IN HIS LIVER, ENZYMES WERE NORMALLEST THEY'LL EVER BE. AND THEN AS HE REGAINED FAT AND REGAINED ENZYME SO THE WEIGHT IS ACTUALLY PROBABLY THE MOST IMPORTANT FLAIR IRRESPECTIVE OF WHAT MEDICATION WE CAN GIVE THEM. WRONG SLIDE AND WITH THAT I WOULD WILL LIKE TO HIGHLIGHT THE DATA I'VE SHOWN YOU AND MEMBERS OF MY LAB, ALL THE MEMBERS FROM THE CLINICAL SECTION OF THE LIVER DISEASE BRANCH UNDER THE LEADERSHIP GUIDANCE OF [INDISCERNIBLE], AND COLLABORATORS FROM THE CLINICIAN FOR IMAGING PATHOLOGY AND SOME OF US COLLABORATING OF COURSE ARE PATIENTS THAT HELP US. THIS IS OUR GROUP AND I HOPE YOU HAVE BETTER IDES OF MARCH. [ APPLAUSE ] >> SO WE HAVE TIME FOR SOME QUESTIONS. >> VERY NICE JARON. THIS IS THE NOTION YOU BROUGHT UP WITH PEOPLE OF AFRICA DESCENT NOT HAVING VERY MUCH, HOW MANY GENOME REQUESTED SPED STUDYINGS OR BOUND CANDIDATE GENES COULD EXPLAIN THESE DIFFERENCES AMONG THESE DIFFERENT TYPES? >> SO THE BIGGEST HIT IN GENOME WIDE STUDIES HAS BEEN WHAT I HAVE SHOWN. AND THERE A PREVALENCE IN POPULATION. 17% VERSES 21 OR 22% OF CAUCASIANS, IT'S NOT ENOUGH TO EXPLAIN THE DIFFERENCE. IT'S NOT ENOUGH TO EXPLAIN THE DIFFERENCE. >> ON YOUR BREATH TEST DOES IT MAKE DIFFERENCE IN THE HUMAN BEING IS FED OR STARVED? FASTING? >> I'M SURE THAT WE STARTED THE FAST AND AFTER AN OVERNIGHT FAST TO SORT OF AND WE FEED THEM A DEFINED MEAL SO WE CAN CONTROL IT. IT'S MUCH MORE DIFFICULT TO DO SOMETHING LIKE THAT AFTER A MEAL BECAUSE THEN, I MEAN THERE ARE ALSO ISSUES WITH ABSORPTION WITH DELAYING OF GASTRIC EMPTYING BY THE PREVIOUS MEAL AND ALL OF THAT. I SHOULD MENTION VERY INTERESTING DATA WITH LABELING STUDIES THAT SUGGEST THAT MAYBE WE SHOULD LOOK AT THEM AFTER THE NEXT PEEL BECAUSE THERE'S DAT THAT SUGGESTS THAT THE FAT FROM MEALS STAYS IN THE INCESTINAL CELLS AND ONLY SECRETED FROM THEM, AND 1 IN THE LEG OF SECRETION OF COURSE WE SEE SOME OF IT BECAUSE WE DON'T SEE LABELS BUT WE ALSO HAVE TO BE PRACTICAL IN THE CLINICAL STYLES. >> OKAY, SO WE HAVE 1 OTHER. >> JUST A FOLLOW UP TO THE C13 EXPERIMENT, WAS THE RESPIRATORY QUOTIENT THE SAME WHEN YOU DID THAT? WAS THE RATE THE SAME IN BOTH GROUPS? SO THE QUESTION IS ARE YOU SEEING A DIFFERENCE IN FUEL PARTICITIONING AND CARBOHYDRATE AND FAT AND WHAT'S BEING BURNED? AND THAT'S INTERESTING IF IF YOU SEE FOR EXAMPLE, THE THERE'S NO DIFFERENCE YOU'RE BURNING THE SAME CARBOHYDRATE FAT AND THE P A LMETRICSITATE [INDISCERNIBLE]. >> THE SHORT ANSWER IS I DON'T KNOW THE LONGER ISAR SW I DON'T KNOW YET AND ANOTHER LONGER ANSWER IS ANOTHER STUDY WE HAVE DHS IS PERFORMED AT A METABOLIC CHAMBER WITH ALMOST THE SAME CHALLENGE MEAL. IT'S A DIFFERENT TRIAL SO NOT EXACTLY THE SAME BUT MORE OR LESS SO WE WILL HAVE--THAT IS NOT FROM THE SAME MOMENT BUT ON THOSE--MOST OF THESE SAME SUBJECTS WE HAVE THE SAME CONTROL THEN, IN FATTY LIVER SO WE SHOULD BE ABLE TO ANSWER THAT QUESTION. >> SO PRIOR TO 1990 WHEN FATTY LIVER WAS [INDISCERNIBLE], NUMEROUS STUDIES SHOWED THAT THE MECHANISM THAT RELATED TO ACID AND REACTIVE OXYGEN SPECIES AND SO FORTH AND SO ON SO MY QUESTION IS WHO HAS NAFL WHO HAS A FEW BEERS ONCE IN A WHILE ISSUE YOU EFFECTIVE IN SCREENING ALL ALCOHOL INTAKE FROM TEASE PATIENTS? AND WHAT WOULD BE THE EFFECT BE IN YOU HAVE A PLC FOR EXAMPLE, MUTATION OR SOME OTHER ENVIRONMENTAL BUSINESS PREDIABETIC, ALL THE THINGS THAT MAKE US SYNDROME, WHAT IF YOU ADD ALCOHOL TO THAT. >> IT'S SOMEWHAT CONFLICTING BUT I THINK THE LEVEL OF EPIDEMIOLOGY, THERE'S A SUGGESTION THAT LOW LEVEL DRINKING MAY BE BENEFICIAL FOR THESE PATIENTS SAME AS FAR CARDIOVASCULAR DISEASE, AND AGAIN WHETHER THIS IS WINE VERSUS BEER OR ALL ALCOHOL IS THE SAME OR OTHER THINGS IN THE DRINK, I DON'T KNOW. HOW GOOD ARE WE AT SCREENING? IT'S UNCLEAR WHAT HOW MANY DRINK. WHAT'S ACCEPTABLE IN THE WEST IS 2 DRINKS A DAY, MAYBE 3 FOR A MAN BUT IT VARIES PER STUDY AND GUIDE LINE TO GUIDELINE. >> SO IT'S NOT LIKE CAESAR'S WIFE. >> ROSANA! >> SO, WHAT DO YOU THINK WE GET THAT HIT THAT 40% HIT EVERY SINGLE STUDY BEEN DONE WITH 1 DRUG, DO YOU THINK BECAUSE WE HAVEN'T FOUND THE RIGHT MECHANISM, MAYBE BECAUSE WE NEED MULTIPLE MECHANISMS TO SEE THE FULL RESOLUTION ON NASH. AN EVEN MORE IMPORTANT QUESTION CAN BE ASKED FROM THE OTHER SITE. OUR NONRESPONDERS JUST NONRESPOONEDDERS OR ARE THEY NONRESPONDERS TO A SPECIFIC MEDICATION. SO IF THE PERSON WAS RESPONDING WOULD THEY ALSO RESPOND OR CAN WE TAYLOR 1 MEDICATION OR NOT, I DON'T KNOW. IT'S STUDY THAT I WOULD LOVE TO DO. >> YEAH, THE PATIENT IS VERY IMPORTANT BECAUSE IT'S NOT ONLY 1 DISEASE, THEY'RE MULTIPLE DISEASES. SO FIRST OF ALL WIN, THANK YOU FOR INVITING ME HERE TODAY AND I WANT TO SAY A FEW WORDS JUST TO CLARIFY WHAT WIN SAID. SO YES I COME FROM ACADEMIA, I'M MD, Ph.D. TRAINED IN DEPARTMENT. I'M NOT AN ADMINISTRATOR, SO I WANT TO MAKE THAT VERY CLEAR. ACTUALLY SINCE I WAS IN MEDICAL SCHOOL, I WANTED TO BE PART OF TRANSLATION. I WANTED TO SEE DRUGS COMING FROM THE BENCH TO THE PATIENTS AND ACTUALLY I BELIEVE THAT'S WHAT GOT ME INTO MEDICAL SCHOOL BECAUSE FROM BENCH TO PATIENT OR SOMETHING LOAMACY THAT, AT THAT TIME THIS WAS NOT SOMETHING THAT PEOPLE TALKED ABOUT. I DECIDED ACTUALLY WHILE I WAS DOING MY Ph.D. THAT I WANT TO GO INTO BIOTECH. I DON'T WANT TO SAY IN ACADEMIA. SO IT WAS VERY DELIBERATE AND THE REASON FOR THAT IS BECAUSE I WANTED TO BE PART OF THE TRANSLATION COMMUNITY. AND I HAVE TO SAY THAT ONLY TOOK ME 20 YEARS BUT THERE'S ALWAYS HOPE AND THAT NOW I ACTUALLY [INDISCERNIBLE], ARE WE ARE ON OUR WAY TO DO IT SO WHAT I WANT TO TALK TODAY IS THE WORK WE HAVE BEEN DOING IN GENERATING INHIBITORS AGAINST THE KEY ENZYME INVOLVING FATTY ACID SYNTHESIS. SO THE TITLE OF MY TALK WHICH IS TRIMMING THE FAT: INHIBITING ACETYL COA CARB BOX LACE TO TREAT NONALCOHOLIC FATTY LIVER. SO THIS IS NASH GOING TO BE THE BIGGEST EPIDEMIC OF THE 21st CENTURY, TELL SURFACE ALL OTHER DECEASES AND WE HAVE TO FIGURE OUT HOW TO TREAT THESE PATIENTS. I THINK THIS IS A VERY GOOD PERCENTAGE OF NASH PATIENTS ARE NOT ALL OBESE AND NOT ALM OF THEM ARE OBESE AND AS WE TALK THERE'S A LOT OF HETEROGENEITY IN THE DISEASE BUT A GREAT PERCENTAGE IS, - BEES AND LIFESTYLE MODIFICATION DOES WORK. IT IS THE BEST WAY TO TREAT NASH BUT THE PUBLICITY IS THAT IT'S NOT SUSTAINABLE. SO LET'S TALK ABOUT THE NUMBERS. WHY IS THAT SUCH A BIG PROBLEM AS YARON SAID THERE'S ABOUT 30% OF ADULTS AND 10% OF CHILDREN NOW IN THE UNITED STATES THAT HAVE NAFL. SO, OKAY? WE TRANSLATE THAT NUMBER, THAT'S ABOUT 80 MILLION PEOPLE. 80 MILLION PEOPLE IN JUST IN THE UNITED STATES. OKAY? AND THEN, FROM THAT, 10-30% WILL DEVELOP NASH, WHICH IS CHARACTERIZED BY INFLAMMATION, APOPEITOSE AND I GUESS FIBROSIS, SO THAT'S ABOUT 16 MILLION PEOPLE, AGAIN 10% OF THOSE CHILDREN 1 MILLION CHILDREN WITH THE RISK OF DEVELOPING CIRRHOSIS. AND THEN WITH WHEN YOU CONTINUE THE MATH, YOU KNOW 20-30% WILL DEVELOP ADVANCED NASH AND CIRRHOSIS AND THEN A PERCENTAGE OF THAT WILL END UP IN LIVER TRANSPLANTATION, THERE'S CARDIOVASCULAR RISK, RIGHT NOW THE ESTIMATE IS ABOUT BY 2025 WILL SPEND 35 BILLION DOLLARS IN TAKING CARE OF THIS PROBLEM. SO WE NEED TO DO SOMETHING NOW. AND WE ALREADY AGREED THAT [INDISCERNIBLE] THAT PROBABLY THIS, NOT THE FAT ITSELF BUT IT'S ACTUALLY THE ACCUMULATION OF FREE FATTY ACIDS IN THE LIVER THAT LEADS TO METABOLITES THAT INDUCE THE STRESS AND NECKROSIS AND FIBROSIS AND HOW DO YOU GET THAT, HOW DO YOU GET THIS PREFATTY ACID. WE TALK ABOUT DIET, YOU KNOW? AND LACK OF EXERCISE AND HAVE YOU ACCESS CARBOHYDRATES AND LIPO GENESIS AND OF COURSE, THE COUNTERPART OF THAT IS INSULIN RESISTANCE. AND I'M GOING TO TAKE YOU BACK 40 YEARS AGO WHEN WE ACTUALLY START UNDERSTANDING MORE ABOUT A CARDIOVASCULAR DISEASE AND UNDERSTANDING MORE THAT CHOLESTEROL WAS THE CULPRIT OF CARDIOVASCULAR DISEASE AND HOW THEY TREAT CHOLESTEROL AND THE FIRST THING WE TAKE PATIENTS BECAUSE THE EGGS ARE BAD FOR YOU, YOU KNOW DECREASE YOUR CHOLESTEROL INTAKE AND THAT DIDN'T SOLVE THE PROBLEM AT ALL AND THEN WE DEVELOP A DRUG THAT MOST OF US USE, STATINS THAT ARE REDUCT ACE ININCREASE IN BODYITORS SO IF YOU CAN'T PRODUCE IN [INDISCERNIBLE], CAN YOU IMPROVE THE CONDITION BY BLOCKING THE ENDOGENOUS PRODUCTION OF FATTY ACIDS. SO HERE COMES MY FAVORITE SLIDE. ACC, AND IT IS IN THE PRODUCTION OF DE NOVO FATTY ACIDS, FATTY ACID SYNTHESIS AND ALSO AN INHIBITOR OF THE OXIDASES, SO IF IT INHIBITS ACC, IT WILL INCREASE THE BETAOXIDATION. SO LET ME TELL YOU ABOUT MORE ABOUT IT. THERE ARE 2 ISOFORMS HERE, ACC1 AND ACC2, ACC1 AND [INDISCERNIBLE] AND ACC2 IS ACTUALLY PRESENT IN THE OUTER MEMBRANE OF THE MITOCHONDRIA IN THIS THE PRESENCE OF OXIDATIVE TISSUES LIKE MUSCLE. BUT THE REALITY IS THAT ACC1 AND 2 ARE IN THIS ALL TISSUES AND IT'S A BLOCKED FORM AND NOT THE OTHER THEY WILL FIND A WAY TO COMPENSATE FOR EACH OTHER BECAUSE IT'S AN ESSENTIAL ENZYME. WHAT THEY DO IS [INDISCERNIBLE] WHICH IS THE FIRST BUILDING BLOCK OF FATTY ACID AND ALSO ENFORCED TO KNOW ABOUT THE NUCLEACE THAT IT INHIBITS PT-1 WHICH IS THE TRANSPORTER INVOLVED IN FATTY SARKS SID TRANSLOCATION AND SO BASICALLY BY DOING THAT BLOCKING THE BETA. VERY SMART. SO IF YOU INHIBIT THE ACC1, WHAT YOU WILL GET IS A DECREASE INSIDE THE SENSORS WITH THE CONCOMITANT CONCLUSION. THE IF YOU THINK ABOUT THAT, THAT'S WHAT HAPPEN WHEN IS YOU EXERCISE. THAT'S EXACTLY WHAT HAPPENS WHEN YOU EXERCISE. AND BY THE WAY, THIS IS [INDISCERNIBLE], WHICH IS ACTUALLY GOING TO BECOME IMPORTANT IN A MINUTE. SO THAT'S OKAY, SO WHAT WE HAVE IS THAT THE ACTUALLY PLOOKING ACC, COULD IMPROVE ON NASH, SO THIS WAS ACTUALLY PUBLISHED NOT A COUPLE OF YEARS AGO, AND IT'S 1 OF THE MOST ELEGANT PAPERS I HAVE EVER READ AND WHAT A GO IS THAT THEY EXPRESS ACTS AS ACCAND THEY DO THAT, THEY DO POINT MUTATIONSOT RESIDUE AS FOR AS EMPTY KINASE, SO THE MP KINASE CAN NO LONGER PHOSPHORYLATE AND IT'S ACC1 AND 2, THEY GENERATE THIS TRANSGENIC MICE AND WHAT DO THEY HAVE NASH? SO THEY HAVE INCREASED TRIGLYCERIDES AND INCREASED FIBROSIS AND DECREASED INSULIN SENSITIVITY. I WILL ALSO TALK ABOUT THE INFLAMMATORY PART WHICH IS AN IMPORTANT PART OF IT. NOW IF YOU USE RNA BASED TECHNOLOGY TO MAX OUT THE ENZYME AND YOU'RE DOCK DOWN ACC1 AND TABOO, YOU INCREASE FATTY ACIDOXIDATION AND DECREASE FATTY ACID. I JUST WANT TO STOP HERE FOR A MOMENT AND PAUSE BECAUSEs THERE'S A LOT OF CONTROVERSIAL DATA OF THE ACC1 IN THE LIVER, AND ACC1 AND 2 IN THE LIVER, AND I--IT'S VERY CONFUSING, IT'S VERY DEPENDENT ON THE BACK GROUND THAT YOU'RE USING FOR THE MICE, I WOULD REFRAIN FROM MAKING 2 MANY CONCLUSIONS FROM THAT, BUT IN THE PAPER THAT'S PUBLISHED RIGHT NOW WITH ACC1 TO KNOCK OUT IN THE LIVER, THEY CLAIM TO SEE AN INCREASE IN LIVER TRIGLYCERIDES IN THE LIVER WHICH VERY MUCH COULD BE USE DUE TO THE MECHANISM THIS TALKS ABOUT THE, LIFE POLICY AND THE FATTY SAIDS GETTING INTO THE LIVER. SOMETHING TO REMEMBER BUT THAT'S NOT WHAT WE SEE WHEN WE PHARMACOLOGICALLY INHIBIT ACC. SO WHAT DOES ACCDO, THAT'S IMPORTANT FOR THE CONVERSION OF MONONUCLEAR NUCLEACE, AND THE ONLY REASON I WILL TURN THIS SLIDE IS BECAUSE THIS IS A 2 SEPARATE ACTION, THIS IS A MULTIBIOTIN CARRIER PROTEIN AND A TRANSCAR BOX LACE DOMAIN AND A IT CARRIES IT FROM 1 SIDE OF THE ENZYME TO THE OTHER SIDE OF THE ENZYME AND THE CAR BOX LACE WHETHER THERE'S CARBON THAT'S PUT IN THE BIOTIN AND THEN IT'S TRANSFERRED TO THE CAR BOX LACE DOMAIN AND THAT DOMAIN ACTUALLY PUT THAT TO MAKE MONONUCLEATE OUT OF IT. SO IF YOU LOOK AT THIS AND A PRIORI, IT'S GOING AFTER THE CARBOXYL DOMAIN OR THE TRANSCORBOX LACE, THEY COULDN'T FIND A WAY TO GET THE CAR BOX LACE, SO WE TOOK AN ORTAGONNAL APPROACH BECAUSE WHAT YOU HAVE AN IS ALOE FERRIC SIZE THAT REGULATES THE PHYSIOLOGICAL INHIBITION OF THE ENZYME BY PHOSPHORYLATION BY THE INDUCED KINASE SO THIS HAS BEEN JUST BEEN POPULAR WHO A COLLABORATOR AND HAS BEEN STUDYING FOR A LONG TIME WHAT HE SHOW SYSTEM THAT WHEN THE THESE 3 ARE FORMULATED--THE POINTER IS NOT WORKING BECAUSE--LET'S SEE, NO. THE SO WHEN I DON'T KNOW IF YOU CAN SEE IT BUT BASICALLY WHEN THE OBESITY DOMAIN IS PHOSPHORYLATED IT CREATES A BUMP, THAT THE DOMAIN WORK AND IT'S AN AWFUL LAB THAT YOU SEE THE DOMAINS OF WHOLE ENZYMES. >> THERE'S 1 CALLED [INDISCERNIBLE] THAT INHIBITS THE ENZYME AND IT'S KNOWN FOR 10 YEARS AND PEOPLE HAVE BEEN TRYING TO TARGET THAT SIZE BUT THEY FAILED TO DO THAT AND I WILL SHOW YOU WHY IN A MENUTE. SETHIS IS JUST THE PHOSPHORYLATION OF THE ADOMAIN OF THE BC DOMAIN TAIL AND BASICALLY THAT PHOSPHATE NOW IS BINDING TO THIS RESIDUE HERE AND BASICALLY BLOCKING THE DIMERIZATION OF THE PROTEIN AND WHAT WE DO, OR ALL INHIBITOR EXACTLY ON THAT POCKET AND BY THE WAY, COORDINATES WITH THE SAME RESIDUE THAT THEY COORDINATE SO OUR INHIBITOR IS DOING IS MIMICKING THE PHYSIOLOGICAL INHIBITION OFF HERE WHICH IS VERY DIFFERENT FROM ALL OTHER INHIBITORS. SO THIS IS ACTUALLY THE TARGETIVATE. AND WHAT YOU --TARGET SITE. WHAT YOU SEE IN GREEN IS CAD WHAT. THE IF YOU DON'T KNOW CHEMISTRY LIKE ME, IT'S LIKE BASICALLY, IT'S VERY BIG MICRO [INDISCERNIBLE] THAT SITS ON THE CORK OF THAT PARTICULAR SITE BUT--AND THE--HERE IS THE RED SPHERES ARE HIGH ENERGY WATER, THESE ARE WATERS THAT ARE TRAPPED IN THE SIDES AND ARE NOT HAPPY. SO THE THEORY GOES THAT IF YOU CAN ACTUALLY DISPLACE THOSE WATERS YOU WILL DECREASE THE AFFINITY OF THE LIGAND FOR THE RESUPPORTOR AND YOU WORK WITH A COMPANY FOR CHEMISTRY AND THE PARTNERS AND THEY CHARACTERIZE THOSE WATERS AND THAT'S WHAT WE DID AND WE WENT AFTER THOSE WATERS AND GENERATE AID MOLECULE THAT'S INCREDIBLE LOAMACYY IMPORTANT. SO THIS MOLECULE IS IN THE CLINIC, WE FINISH PHASE 1 STUDY, PHASE 2 READY AND PRESENTING OUR CLINICAL DATEDDA AT [INDISCERNIBLE] PARSE LONE--BARCELONA IN A MONTH. BUT THAT BINDS THE SAME TIE AND PRECLUDES THE PROTEIN, VERY ACTIVE AND IT'S ABOUT SINGLE DIGITS NANO MOLAR AND THAT TRANSLATEDS NICELY WITH THE POTENCY IN BOTH THE [INDISCERNIBLE] ASSAY AND THE ANIMAL MODEL AND I WANT TO CALL YOUR ATTENTION TO THIS INHIBITION OF THE FATTY ASIT SYNTHESIS. SO WHAT WE DO THERE IS WE INFUSE THE ANIMALS WITH C13 IN THAT AND THE CHROMATIN AND WE DO EXACTLY THE SAME THING IN HUMANS SO WHAT I WILL TELL YOU IS THAT THOSE THAT WE'RE USING IN THE ANIMALS TO BLOCK THE PRODUCTION OF [INDISCERNIBLE] IS BASICALLY THE SAME DOSE THAT WE USE IN THE RAT TO BLOCK THE PROTECTION, IT'S THE SAME DOSE TRANSLATED INTO THE HUMANS TO DO THAT. SO WE CAN NOW CALCULATE EXACTLY WHAT THE CENTER FOR EXCELLENCE ON AGINGIVE DOSE IS. TO PRODUCE NASH YOU NEED 3 THINGS AND USING INFLAMMATION AND A POTENT APOPEITOSEIS AND FIBROSIS. AND THE ONLY WAY THAT YOU ARE GOING TO BE ABLE TO TREAT NASH IS IF YOU CAN ACTUALLY BLOCK EACH 1 OF THE PROCESSES, JUST LIKE 1 OR THE OTHER JUST MAY NOT BE SUFFICIENT BUT WE TOOK AN APPROACH FOR THE MECHANISTIC MODEL OR STUDY INFLAMMATION AND FIBROSIS AND WHAT I'M SHOWING HERE IS THAT WE HAVE A VERY NICE PRODUCTION IN THE PRODUCTION OF MONONUCLEACE IN THE LIVER AND MUSCLE THAT'S THOSE RESPONSES AND THAT TRANSLATES NICELY TO THE FATTYY ACID SYNTHESIS IN THE LIVER AS I TALKED ABOUT BEFORE AND ALSO INCREASED IN FATTY ACID OXIDATION: WE DEVELOP THOSE RESPONSES. WE DID SEVERAL MODELS, 14 DAY STUDY, 28 DAY OLD STUDIES HIGH FAT, HIGH SUCROSE, IN ALL OF THESE STUDIES WHAT WE GOT WAS DECREASE IN FREE FATTY LIVER ACIDS AND DECREASE IN TRIGLYCERIDES AND VERY DIFFERENT FROM THE FINDINGS WE ALSO SEE A DECREASE IN CHOLESTEROL THAT TRANSLATE INTOED HUMANS SO OUR HUMAN SUBJECT VS DECREASED CHOLESTEROL NOT INCREASED CHOLESTEROL. THE SECOND THOUGH WE HAVE SHOWN THAT WE DECREASE APOPTOSIS IN THE LIVER, NOW CAN WE DECREASE INFLAMMATION AND FIBROSIS. AND WE--DECIDE TO TAKE A DIFFERENT APPROACH IN TERMS THAT WE WANT TO SEPARATE THOSE FROM INFLAMMATION AND FIBROSIS. BECAUSE 1 OF THE CREVICES WE GOT WAS OH EVERYTHING IS DOING THIS BECAUSE OF DECREASING FACT OR DECREASING BODY WEIGHT OR WHATEVER. THE AND WE WANT TO SAY NO. IT'S A DIRECT IMPACT AND INFLAMMATION AND FIBROSIS, SO WE USE THIS RAT MODEL THAT WILL CAPITULATE THIS, AND YOU SEE HAVE THE EARLY FIBROSIS AND THE HAVE THE HEPATOCYTE BALOONS AND YOU SEE THE LEVEL OF INFLAMMATION IS THERE, AND BY 18 WEEKS ACTUALLY YOU SEE IT WORSENS AND YOU ALSO HAVE CARCINOMA SO THIS GOES THROUGH ALL THE THINGS, ALL THE WAY TO CANCER. AND WHAT YOU CAN SEE HERE IS WHEN THE ANIMALS ARE TREATED WITH THE INHIBITOR WE SEE THE DECREASE IN THE PRODUCTION OF THE SMOOTH MUSCLE ACTION IN THE LIVER AND THAT'S TRANSLATED NOT ONLY AT THE PROTEIN LEVEL BUT ALSO AT THE GENE EXPRESSION LEVEL: BASICALLY SHOWING THAT WE'RE BLOCKING THE ACTIVATION AND ACTUALLY DATA THAT I'M NOT SHOWING HERE WE HAVE THE DATA ALSO THAT'S DIRECT IMPACT OF THE BASIS INHIBITION, OF STELLATE CELLS AND THE OTHER PIECE IS THAT WE LOOK AT INFLAMMATORY MARKERS AND OTHER FIBROSIS MARKERS IN WHAT I CAN TELL YOU IS THAT DM INDUCE ALL THIS INFLAMMATION MARKERS FOR EXAMPLE, TNF ALPHA AND THEN BASICALLY WE SEE A DOSE RESPONSE OF REDUCTION IN ALL THE INFLAMMATION MARKERS AND WE ALSO SEE IN THE THOSE RESPONSIVE REDUCTION IN FIBROSIS. THAT PIQUED OUR INTEREST BECAUSE WHY ARE WE SEEING AN IMPACT IN INFLAMMATION AND 1 THEN I WANT TO BRING UP IS TH17, I DON'T KNOW IF YOU ARE FAMILIAR WITH TH17 BUT THE EFFECTOR CELLS, INFLAMMATORY CELLS AND THEY HAVEN'T ACTUALLY BEEN IMPLICATED IN THE PROGRESSION OF NASH, AND IT'S A BLACK 17, YOU CAN HAVE ALL THE FAT IN THE LIVER AND ALL THE FATTY ACIDS IN THE LIVER, YOU CANNOT PROGRESS TO NASH AND THEN WHEN YOU LOOK TO HUMANS, THERE IS AN INCREASE, THIS IS ALL TERMINOLOGY RIGHT NOW. BUT IT'S A HUGE INCREASE IN HEPATIC TH17 CELLS AND RA-GAMMA AND IL17 AND IL-21 AND IL23 AND DOLLAR'S A WHOLE BODY THAT'S EXPLORING THE ROLE OF TH17 ISN'T LIVER. AND IN ADDITION TO THAT, THERE'S 2 PAPERS COMING OUT RECENTLY SHOWING THAT THE ACTIVITY IS KEY FOR TH17 FUNCTION. THE FIRST PAPER IS WHAT THEY SAW IS THAT THE INHIBITS TO THE AND ACTUALLY THROUGH THE TREG ARE THE SUPPRESSOR [INDISCERNIBLE] ARE GOOD ACTORS. AND THEN IN CELL, BASICALLY WHAT THEY SHOW IS THAT THE ACTIVITY IS REQUIRED FOR THE BIOSYNTHESIS OF THE ENDOGENOUS LIGAND OF GAMMA T WHICH IS REQUIRED FOR THR 17 DIFFERENTIATION AND WHAT WE SHOWED HERE IS WE HAVE A BULL DOSE RESPONSIVE DECREASE IN TH17 DECREASE IN VIVO AND INVITTO--SORRY AND WHAT WE'RE NOT SHOWING HERE IS A AN INCREASE IN TREG. WE HAVE DONE MODELS OF A EA17 MODEL AND WE COMPLETELY LOST EACE IN THIS ANIMAL. AM SHOWING WE'RE BLOCKING TH17 INVERIFY O AS WELL AND THIS IS IN THE LIVER. --FOR THE FATTY ACIDS IN THE LIVER BUT THEY ALTS BLOCK INFLAMMATION IN THE LIVER AND THEY ALSO BLOKE FIBROSIS IN THE LIVER, THESE ARE ALL PAPGHT WAYS THAT ARE REQUIRED FOR CAN THE [INDISCERNIBLE]. SO IN SUMMARY, WE HAVE THE FIRST IN CLASS ALOESTERRIC ACC1 AND 2 INHIBITOR AND WE'RE EXCITED ABOUT THAT AND THIS IS A LOT [INDISCERNIBLE] 1 THING I FORGOT TO MENTION IS THAT IT'S VERY IMPORTANT, BUT THE TARGET RELEVANCY TISSUES AND THEY'RE A BIT OF THE MUSCLE, YOU DON'T WANT IT EVERYWHERE AND THAT WE IMPACT THE KEY PATHOGENIC PROCESS OF BOTH NASH. AS I MENTIONED BEFORE WE ARE NOW PHASE 2 READY AND WE HAVE JUST BEEN GRANTED FAST TRACK DESIGNATION BY THE FDA SO WE'RE TRYING TO RAISE THIS BUT WHEY WANT TO TELL SURVEYS WE JUST REMIND YOU CURRENCY AND AND AROUND THE WORLD AND MOSTLY THE UNITED STATES AND EUROPE, AND THEN IN TERMS OF ALL THE COMPOUNDS THATTURE CURRENTLY IN THE CLINIC FOR NASH THIS, IS A SUMMARY OF THE COMPOUNDS AND THE ONLY THING I WANT TO SAY IS THAT THEY EITHER METABOLIC MODULATORS OR THE INFLAMMATORYS, THERE IS SOMEWHAT MORE DONE WITH ANTIOXIDANT BUT COMCOMBINE THE ANTIOXIDANT WITH THE OTHER DRUGS AND THAT'S WHY I ASK THE QUESTION ABOUT THE COMBINATION. LET SO THANK YOU VERY MUCH, I WANT TO ACKNOWLEDGE MY COLLEAGUES THAT DID THE WORK. NIMBUS AND OTHER PLACES, WE DEVELOP STRONG COLLABORATIONS AND [INDISCERNIBLE] THIS OTHER BIOLOGY TOOK THE COMPOUND FROM THE COMPUTER FIRST IN THE RATTINGS AND NOW INTO MAN. SO I DIDN'T GO FROM THE BENCH TO THE BODY SIDE, BUT I WENT FROM COMPUTER TO BODY SIDE. YOU KNOW SO THANK YOU VERY MUCH. [ APPLAUSE ] >> [INDISCERNIBLE] >> THAT IS A GREAT QUESTION. AND THERE'S A LOT OF DISCUSSION ABOUT THAT RIGHT NOW. FROM THE FDA, AND THE EMA, SO RIGHT NOW AS YARON, ALL WE HAVE IS THE NEUROLOGICAL THERAPY END POINT AND THESE ARE BASICALLY FOR THAT COURSE AND YOU HAVE TO SHOW A DECREASE IN HEPATOCYTES SO JUST FINDING A DECREASING PATH IS NOT ENOUGH ANYMORE, YOU HAVE TO SHOW HEPATOCYTE BALLOONING AND YOU HAVE ON SHOW A DECREASE IN FIBROSIS AND WHAT THE WHOLE COMMUNITY IS WORKING, LIKE WORKING VERY HARD VERY FAR IS WHAT ARE THE BIOMARKERS, THAT ARE GOING TO BE ABLE TO USE TO PREDICT PROGRESSION OFF THIS BUT WE'RE NOT THERE YET, THERE ARE SOME CANDIDATES BUT THEY'RE NOT GOOD ENOUGH. AND YOU WANT TO ADD ANYTHING TO THAT? THERE'S IMAGING ALSO BUT THE IMAGING, YOU KNOW IT'S NOT-- >> OKAY, I HAVE TO AGREE. THE 1 SHARED MEETING WEAN THE FDA AND ASSOCIATION FOR STUDY OF LIVER DISEASES 2 OR 3 YEARS AGO AND DIRECT COMMENDATION WAS TO GO WITH NASH RESOLUTION WHICH THEN TURNED OUT TO BE A VERY DIFFICULT END POINT TO ACHIEVING IN THE SUBSEQUENT STUDIES AND IT'S NOT [INDISCERNIBLE] FOR THE END POINT BECAUSE THEY WANTED TO IT'S BECAUSE THAT'S WHAT THE FDA SAID THEY AGREED THAT'S--IT'S REALLY WHAT WE WOULD LIKE TO ACHIEVE BUT IT SEEMS THAT IT'S GOING TO BE VERY DIFFICULT TO GET THERE. >> SO WHAT HAPPENED IS WHEN THEY STARTED PHASE 3, THEY'RE GOING AFTER CO PRIME PRIMARY END PINTS, SO NO FIBROSIS OR RESLUGESSAL FIBROSIS AFTER NASH. NOW BENEFIT FOR PHASE 3, THEY WILL ONLY WORK 1 PRIMARY END POINT AND WORKING OFF FIBROSIS, THERE'S STILL A LOT OF DISCUSSION AND WHAT THE FIELD HOPE SYSTEM IN THE NEXT 2 OR 3 YEARS AS WE DO THIS PHASE 3 STUDY, THAT WAS WE'RE GOING TO DEVELOP THE BIOMARKERS THAT ARE GOING TO BE USED. I MEAN [INDISCERNIBLE] CLAIMS THEY HAVE MicroRNA BIOMARKER THAT THEY CAN USE IN THEIR TRIALS, BUT NOBODY HAS SEEN IT SO THERE'S STILL A LOT OF SKEPTICISM BUT 1 THING I WILL SAY IS THAT THE FDA AND AMA IS WORKING VERY HARD WITH THE COMMUNITY TRYING TO DEVELOP A NEW WAY OF DOING THIS AND ACTUALLY THERE WAS LIVER FORUM, I DON'T KNOW IF APPROXIMATE YOU KNOW ABOUT THAT BUT EVERY MEDING NAFL, AND [INDISCERNIBLE] MEETING THE FDA AND EMA PARTICIPATE AND THEY HAVE WORKSHOPS INVOLVING PEOPLE FROM INDUSTRY AND ACADEMIA TO TRY TO SOLVE THIS PROBLEM. >> SO ROSANA WHAT'S THE METABOLISM OF THE DRUG. >> DECREASE IS APPARENT BY THE BIOME. THERE'S NO METABOLISM TO SPEAK OF. IT'S A COMPOUND SECRETED BY THE BIOME. IT GOES TO THE LIVER AND THEN EVENTUALLY COMING OUT IN THE BIOME. AND WHY DOES IT GO TO THE LIVER? >> BECAUSE IT TAKES ADVANTAGE OF OATP. YEAH, WE DESIGNED IT WE SPECIFICALLY DESIGNED THIS DRUG TO GO TO THE LIVER CHEMICALLY, SO THERE'S MORE CHEMISTRY. >> WHAT WHAT THE BASIS WAS-- >> THE CARBOXYLIC ACID, IN THE RANK AND BASICALLY THAT STICKS OUT [INDISCERNIBLE] AND BUT THERE ARE 50 ATPs AND-- >> ONE, 2, AND 3, IT'S JUST 1, 2, AND 3. THE. >> AMAZING. >> YEAH, AND WE HAVE A LOT OF [INDISCERNIBLE] CHARACTERIDESSATION ALSO TRANSPORT MECHANISM. >> SO WE REGARDING THE OATP TRANSFERASE, YOU WILL STILL SEE THE EFFECT ON NO HEPATITIS E O O SIGHT CELLS BECAUSE IT SEEMS LIKE THERE'S AT LEAST IT LOOKS LIKE THERE'S DIRECT EFFECT ON T-CELLS AND DIRECT EFFECT ON ATC IN STELLATE CELLS, WILL THAT BE TRUE ALSO IN THE HUMAN IN VIVO? >> WE DON'T KNOW THAT. SO THE ONLY THING I CAN SAY IS THAT WE HAVE DONE THE INVITRO STUDY WITH HUMAN TH17 CELLS AND IN HUMAN STELLATE CELLS AND THE ANSWER IS YES. OKAY? AND THE WAY THAT WE--THAT WE HAVE DONE THE HUMAN STELLATE CELL SYSTEM VERY INTERESTING. WE'RE COLLABORATINGOT [INDISCERNIBLE]. AND IT GETS THE BIOPSY THAT'S BARIATRIC SURGERY SORE WE'RE GETTING THE STELLATE CELLS FROM. SO WHICH IS GREAT BECAUSE THEY ARE VERY ACTIVATED. BUT WE HAVE NO WAY TO KNOW THAT UNTIL [INDISCERNIBLE]. LET WHAT I CAN SAY ABOUT HUMANS IS THAT [INDISCERNIBLE] OF THE RAT OF THE ACID ACE, YOU CAN [INDISCERNIBLE] IN HUMAN AND WE HAVE USED HERMANS WITH THE [INDISCERNIBLE] AND WE HAVE THE [INDISCERNIBLE] AND THE NEXT DAY WE GAVE THOME COLLATE FOR 10 HOURS AND THEN A DOSE EVERY HALF HOUR TO INDUCE AND FATY ACID AND BASICALLY WE CAN SEE THOSE RESPONSES RE--THE [INDISCERNIBLE] ENZYMES SO THERE'S MORE AND MORE DATA THAT SUGGEST THAT THERE'S PARTITIONING OF THE METABOLISM BASED ON ACTUALLY CELLULAR LOCATION THAT YOU HAVE ENZYME CLUSTER TOGETHER AND THE PALM FROM THE ADIPOSE TISSUE WILL BE METABOLIZED GENERALLY FROM THE LIPO GENESIS, EVEN IF IT'S THE SAME INSWROAM SO IF AND--[INDISCERNIBLE] >> WE DO STUDIES IN CULTURE AND [INDISCERNIBLE] DIFFERENTIATION BUT WE DON'T KNOW YET. YEAH. THAT'S A GREAT QUESTION. THE REASON TO BASICALLY BLOCK THE VOTE IS BECAUSE THERE'S SO MUCH CONFUSION WITH THE KNOCK OUT AND WE KNOW THAT 1 CAN COMPENSATE FOR THE OTHER THAT IT WAS THE TYPE OF BLOCK, BUT THE TISSUE TARGETEDS. YOU SEE, SO TO AVOID SOME OF THE OTHER ISSUES. >> WELL, THANK YOU BOTH. MENT AND THIS WILL BE A WORK IN PROGRESS. >> OH YEAH.