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NOW ON TO TODAY'S TALK.
THE CONTEMPORARY CLINICAL
MEDICINE GREAT TEACHERS GRAND
ROUNDS IS A SPECIAL SERIES
WITHIN THE CLINICAL CENTER GRAND
ROUNDS PROGRAM.
AS CONCEIVED BY THE FIRST
COMMITTEE CHAIR OF THE GREAT
TEACHERS COMMITTEE, DR. PAUL
PLATZ, DISTINGUISHED SCIENTIST
EEMERITUS OF NIAMS, TO PRESENT N
TOPICS AND IDEAS ABOUT WHICH
THEY ARE PASSIONATE TO SHARE
THEIR REFLECTIONS WITH US AND TO
INSPIRE YOUNG INVESTIGATORS IN
THE PURSUIT OF CAREERS IN THE
FIELD OF BIOMEDICAL RESEARCH.
OUR SPEAKER TODAY IS
DR. ELIZABETH PARKS, SCHOOL OF
MEDICINE AT THE UNIVERSITY OF
MISSOURI.
SHE'S ALSO THE ASSOCIATE
DIRECTOR OF THE CLINICAL
TRANSLATIONAL SCIENCE UNIT AND
AN INVESTIGATOR IN THE
UNIVERSITY'S NEXT GEN PRECISION
HEALTH INITIATIVE.
DR. PARKS RECEIVES HER BACHELOR
OF SCIENCE AT THE UNIVERSITY OF
WISCONSIN-MADISON AND EARNED HER
PH.D. IN NUTRITIONAL
BIOCHEMISTRY AT THE UNIVERSITY
OF CALIFORNIA DAVIS.
SHORTLY AFTER, SHE COMPLETED HER
POSTDOCTORAL FELLOWSHIP AT UC
BERKELEY AND UC SAN FRANCISCO.
IN 2013, SHE MOVED TO THE
UNIVERSITY OF MISSOURI.
DR. PARKS' RESEARCH FOCUSES ON
HOW UNDERSTANDING HOW THE FOOD
WE EAT IS PROCESSED IN THE BODY
TO BENEFIT HEALTH, AND HOW FOOD
CAN ALSO CONTRIBUTE TO THE
PROGRESSION OF DISEASES SUCH AS
OBESITY, PREDIABETES AND
DIABETES.
THE MAJOR RESEARCH CONTRIBUTIONS
OF THE PARKS LAB EMANATE FROM
THE DEVELOPMENT OF NOVEL
TECHNIQUES TO MEASURE THE
ABSORPTION AND DISPOSAL OF
DIETARY FATS, CARBOHYDRATES AND
PROTEINS IN BOTH HUMANS AND IN
ANIMAL MODELS.
OVER THE PAST 24 YEARS,
DR. PARKS HAS DEVELOPED METHODS
USING COMBINATIONS OF MULTIPLE
STABLE ISOTOPES, COUPLED WITH
MATHEMATICAL MODELING TO
ESTABLISH A NON-STEADY STATE
MODEL OF POST MEAL METABOLISM.
USING THIS MODEL, SHE'S SHOWN
THAT IN CONTRAST TO RODENTS, A
SIGNIFICANT AMOUNT OF MEAL FAT
CAN CYCLE THROUGH THE LIVER IN
HEALTHY HUMANS.
HER LAB'S SEMINAL CONTRIBUTIONS
HAVE INCLUDED UNDERSTANDING HOW
DIETARY SUGARS, WHICH CAN BE
MADE INTO FAT IN THE LIVER,
SIGNIFICANTLY CONTRIBUTE TO
METABOLIC DYSFUNCTION ASSOCIATED
STEATOHEPATITIS OR MASH.
DR. PARKS HAS HELD LEADERSHIP
POSITIONS IN THE AMERICAN
SOCIETY FOR NUTRITION AND WAS
PRESIDENT OF THE OBESITY SOCIETY
IN 2 2023.
SHE'S A FELLOW OF THE AMERICAN
HEART ASSOCIATION AND THE
OBESITY SOCIETY, AND HAS BEEN A
STANDING MEMBER OF NIH GRANT
REVIEW COMMITTEES FOCUSING ON
METABOLISM, DIABETES AND
OBESITY.
SHE'S ALSO AN AD HOC MEMBER AND
CHAIR OF NUMEROUS NIH REVIEW
COMMITTEES.
THE TITLE OF DR. PARKS'
PRESENTATION TODAY IS -- PLEASE
JOIN ME IN WELCOMING TODAY'S
GRAND ROUND SPEAKER,
DR. ELIZABETH PARKS.
>> THANK YOU VERY MUCH AND IT'S
GOOD TO BE HERE.
I HAVE LEARNED A LOT TODAY.
I'D LIKE TO SHARE WITH YOU SOME
THOSE I HAVE ON DEPOSITS OF
FATTY LIVER DISEASE.
MY EMAIL IS IN THE UPPER
RIGHT-HAND CORNER AND CONFLICT
OF INTEREST IS IMPORTANT FOR ME
TO DISCLOSE.
I CONSULT WITH BOTH THE
PHARMACEUTICAL INDUSTRY AND ALSO
THE FOOD INDUSTRY, NONE OF THE
INFORMATION I'M GOING TO GIVE
TODAY RELATES TO THAT.
SOY WASO I WANT TO START WITH AE
FROM A NOBLE LAUREATE 120 YEARS
AGO.
IT IS NOT ACCIDENTAL THAT ALL
PHENOMENON OF HUMAN LIFE ARE
DOMINATED BY THE SEARCH FOR
DAILY BREAD.
PRECISE KNOWLEDGE OF WHAT
HAPPENS TO FOOD ENTERING THE
ORGANISM MUST BE THE SUBJECT OF
IDEAL PHYSIOLOGY, THE PHYSIOLOGY
OF THE FUTURE.
AND IT STILL IS WHY WE CHOOSE TO
EAT AND WHAT WE EAT IS STILL THE
PHYSIOLOGY OF THE FUTURE.
I STUDY THE NON-EQUILIBRIUM
STEADY STATE.
RICHARD FINEMAN SAID THIS IS
WHEN ALL THE FAST THINGS HAVE
HAPPENED BUT THE SLOW THINGS
HAVE NOT.
AND WHAT HE MEANS BY THAT IS
EVEN WHEN HE HUMANS ARE FASTING,
WE ARE ADAPTING.
WE ARE CONTINUALLY ADAPTING TO
EVERY HOUR THAT WE DO NOT EAT.
AND HUMANS ARE SYSTEMS
ANALYZERS, SO I'M GOING TO TALK
TODAY ABOUT LOOKING AT SYSTEMS
AS THEY CHANGE.
WE WATCH THE WEATHER REPORT ON
THE NEWS AND WE ARE NOT
CHALLENGED BY THE PRESENTATION
OF THAT COMPLEXITY.
THERE'S LOTS OF VARIABILITY
THERE ON THE WEATHER, THERE'S
LOTS OF DATA, AND THE WEATHER
MODEL HELPS US PREDICT THE
FUTURE.
INDIVIDUALS ANALYSES OF THE
COMPLEXITY IN THE WORLD AROUND
US SHOULD THEN COME NATURALLY,
BECAUSE WE ARE SYSTEMS
ANALYZERS, BUT SOMEHOW IN
BIOLOGY, MODELING OF SYSTEMS HAS
NOT BEEN UNIVERSALLY ACCEPTED,
RATHER THE CULTURE CONTINUES TO
FOCUS ON BREAKING DOWN SYSTEMS
TO A SINGLE MEASURABLE UNIT.
THIS IS BECAUSE MOST OF OUR
MEASURING TOOLS DO NOT CAPTURE
THE FLUX OF MOLECULES IN THE
BODY.
WE MEASURE CONCENTRATION REALLY,
REALLY WELL, BUT NOT MOVEMENT OF
MOLECULES.
SOME PIECES OF DATA ARE HARDER
TO OBTAIN THAN OTHERS, AND WE
NEED TO EXPAND OUR METHODS TO BE
ABLE TO COLLECT THESE RIGHT
PIECES OF INFORMATION AT THE
RIGHT TIME.
AND THIS IS WHAT I'M GOING TO
DESCRIBE TODAY.
SOME OF OUR METHODS THAT WE'VE
WORKED ON OVER THE LAST 25 YEARS
TO BE ABLE TO CAPTURE THE VIDEO
OF THE BODY'S METABOLISM AS
OPPOSED TO A SNAPSHOT.
WE NEED BOTH DYNAMIC MODELS AND
ADAPTIVE BEHAVIORAL MODELS AS
WELL.
AND LASTLY, IN THE END, AS THE
MODELING PROCESS HAS HELPED US
PUT OUT TO THE COMMUNITY
TESTABLE PREDICTIONS, AND I'VE
OVER THE YEARS HAD LOTS OF
PEOPLE COME UP TO ME AT
CONFERENCES AND SAY, WE STUDIED
THIS BECAUSE IT WAS SUGGESTED IN
THE PAPER THAT YOU PUBLISHED AND
THAT'S EXACTLY WHAT WE WANT TO
DO.
SO IN THE PRESENTATION OUTLINE,
WE'RE GOING TO FOCUS FIRST ON
LIPID THAT'S MADE IN THE LIVER,
AND THIS IS CALLED DE NOVO
LIPOGENESIS, AND HOW IT CONTROLS
LIVER LIPID STORAGE.
I'M GOING TO THEN SHOW YOU SOME
DATA FROM INDIVIDUAL RESPONSES
OF OVEREATING, AND THEN TALK A
LITTLE BIT ABOUT HOW DE NOVO
LIPOGENESIS CONTRIBUTES TO LIVER
DISEASE.
THEN WE'LL SWITCH TO THE
PERIPHERY, ADIPOSE FATTY ACID
FLUX.
WE USE THIS MODEL TO DETERMINE
THE ROLE OF INSULIN UPTAKE OF
FREE FATTY ACIDS IN THE
PERIPHERY.
AND THEN I'LL SHOW YOU SOME
TREATMENTS TO IMPROVE FATTY
LIVER DISEASE.
I'M GOING TO TALK ABOUT ENERGY
RESTRICTION ALONE, DIET, AND
THEN DIET PLUS EXERCISE.
SO LET'S GET STARTED.
THIS IS A SLIDE WITH THE LIVER
AT THE CENTER.
THE ADIPOSE TISSUE IS DOWN THERE
ON THE RIGHT.
AND THE INTESTINE UP ON THE LEFT
AND THE MUSCLE, AND I APOLOGIZE
TO THOSE OF YOU WHO STUDY THE
BRAIN, THERE ISN'T A BRAIN ON
HERE.
WE'RE GOING TO TALK ABOUT FLUX
OF NUTRIENTS BETWEEN THESE FOUR
ORGANS.
WHEN WILL I FIRST STARTED TO
DEVELOP THIS MODEL, I WANTED TO
KNOW WHERE DID HEPATIC LIPID
DROPLETS COME FROM.
THEY'RE ELEVATED IN OBESITY, IN
DIABETES.
WHY DO THEY BUILD UP AND WHERE
DOES THAT FAT COME FROM BECAUSE
IF WE COULD FIGURE THAT OUT,
THEN WE COULD MOVE TO A
TREATMENT.
AND ONE OF THE FIRST PLACES WE
DISCOVERED WAS THAT NEW FAT MADE
FROM DIETARY SUGARS CONTRIBUTED
SIGNIFICANTLY TO THIS POOL.
SECOND, WE ASKED WHETHER DIETARY
FAT COULD CAUSE FATTY LIVER AS
WELL, AND THEN THIRD, THE ONE
THAT'S BEEN DOWN THERE IN THE
RIGHT-HAND CORNER IS THE
ADIPOSE.
AND MANY SCIENTISTS BELIEVE THAT
FATTY LIVER IS CAUSED BY TOO
MUCH BODY FAT, AND AS I'LL SHOW
YOU, ADIPOSE FATTY ACID FLUX TO
THE LIVER IS A DOMINANT SOURCE,
BUT IT IS NOT EXACTLY THE
CONTROLLING SOURCE OF WHETHER OR
NOT THE FAT GETS STORED IN THE
LIVER.
I'M ALSO GOING TO SHOW YOU THE
INEFA MODEL WILL DEMONSTRATE
THIS PATHWAY OF FREE FATTY ACIDS
FROM THE ADIPOSE BEING TAKEN UP
INTO THE PERIPHERY, THAT GREEN
LINE THERE.
SO WHAT IS DE NOVO LIPOGENESIS?
DE NOVO LIPOGENESIS IS WHEN WE
FIND A NEW FAT IN THE LIVER THAT
DIDN'T COME TO THE LUFER AS A LA
FAT ALREADY.
IF I EAT BUTTER, A FAT, I COULD
GET THAT FAT STORED IN MY LIVER.
THAT'S ONE WAY YOU COULD DO
THIS.
BUT DE NOVO LIPOGENESIS IS THAT
WHEN ONE CONSUMES SUGARS, THEY
GO DOWN GLYCOLYSIS AND THEIR
BUILDING BLOCKS ARE TAKEN APART
AND PUT BACK TOGETHER AS A NEW
FATTY ACID.
WHEN WE FIRST STARTED THIS WORK,
I WAS FOCUSING ON THIS STEADY
STATE, SO I WANTED TO SET UP A
SITUATION WHERE SUBJECTS WERE
CONTINUOUSLY FED FOR NINE HOURS.
IT WAS 11 HOURS ACTUALLY.
AND SO WE PUT AN I.V. LINE IN
AND DREW BLOOD ALL NIGHT, AND
THEN WE FED THEM THROUGH A
REALLY TINY TUBE, DUODENAL TUBE,
NOT AN NG TUBE, INTO THE UPPER
INTESTINE, AND I HAD BEEN
LABELING LIPOGENESIS.
AND SO WHAT YOU SEE HERE ON THE
LEFT-HAND SIDE IS THE PERCENT OF
FATTY ACIDS COMING OUT OF THE
LIVER THAT WERE MADE FROM SUGAR.
AND THE FIRST TIME I SAW THIS, I
THOUGHT, THERE'S A LOT HERE.
EACH ONE OF THESE LINES IS A
PERSON, AND YOU CAN SEE THE HUGE
VARIABILITY IN THIS PATHWAY
BETWEEN PEOPLE.
YOU CAN GET A SENSE THAT
LIPOGENESIS IS SUPPRESSED WITH
FASTING ALL NIGHT LONG.
THE THIRD POINT IS THAT IT'S
HIGHEST AT ABOUT 1:00 IN THE
MORNING.
SO WE'RE MAKING THE MOST FAT OUT
OF SUGAR IN THE MIDDLE OF THE
NIGHT WHILE WE'RE SLEEPING.
THEN WE TURNED ON THE FEEDING
TUBE, AND SOME OF THESE
INDIVIDUALS TURNED ON THIS
PATHWAY JUST -- IT SHOT UP LIKE
A ROCKET, AND OTHER SUBJECTS,
THAT GREEN LINE THERE ON THE
VERY BOTTOM, THAT PERSON'S LIVER
HARDLY TOOK ANY SUGAR AND MADE
FAT OUT OF IT.
SO WHAT PREDICTS THIS?
IT'S NOT AGE.
THERE WAS A 35-YEAR-OLD AT THE
TOP UP THERE AND A 38-YEAR-OLD
AT THE VERY BOTTOM.
THIS WAS THE FIRST TIME THERE'S
ANY KIND OF STUDY LIKE THIS HAD
EVER BEEN DONE, AND I THOUGHT
MAYBE BODY FAT WOULD CAUSE THAT
LIPOGENESIS TO BE HIGHER AND
THAT WAS NOT THE CASE.
RIGHT IN THE MIDDLE THERE, YOU
CAN SEE THIS 23-YEAR-OLD WHO'S
GOT 7% BODY FAT.
I WILL NEVER FORGET HIM.
HE WAS A COLLEGIATELY RANKED
INTERNATIONALLY KNOWN SOCCER
REFEREE.
THIS GUY RAN ALL WEEK LONG AND
YOU CAN SEE IF YOU CAN LOOK AT
THE PINK LINE, HE STARTS VERY
HIGH AT MIDNIGHT AND WITH
FASTING, HE SUPPRESSES THIS
PATHWAY ALMOST DOWN TO REALLY
LOW LEVELS, AND THEN THE MINUTE
WE STARTED TO FEED HIM, HE
STARTED TO MAKE FAT FROM SUGAR.
SO LET'S LOOK AT LIPOGENESIS
PATTERNS IN HEALTHY INDIVIDUALS.
WE DID A STUDY WHERE WE FED AN
ORAL GLUCOSE TOLERANCE TEST AND
MY SENSE WAS THAT FRUCTOSE WOULD
BE MORE LIPOGENIC THAN GLUCOSE.
SO I STARTED TO REPLACE THE
GLUCOSE WITH FRUCTOSE.
SO THE PINK DATA ARE HALF
FRUCTOSE, HALF GLUCOSE, AND THE
BLUE ARE 75% FRUCTOSE.
AND THESE ARE THE GLUCOSE
CONCENTRATIONS.
WE GAVE THESE CARBOHYDRATE
BOLUSES AT BREAKFAST AND THEN WE
FED THE STANDARDIZED LUNCH EVERY
TIME THEY CAME BACK, THEY GOT
EXACTLY THE SAME LUNCH.
THERE ARE THE INSULIN RESPONSES
AND OF COURSE INSULIN IS HIGHEST
WHEN JUST GLUCOSE WAS FED.
AND THEN HERE ARE THE LIPOGENIC
DATA, AND THE GLUCOSE IN AN ORAL
GLUCOSE TOLERANCE TEST, THE
BLACK CIRCLES ON THE BOTTOM
HARDLY STIMULATED THIS PATHWAY
AT ALL.
BUT YOU CAN START TO APPRECIATE
THE LIPOGENIC POTENTIAL OF
FRUCTOSE.
HERE ARE SOME OTHER DATA WHERE
WE FED TWO MEALS, IDENTICAL
MEALS AT 7:00 IN THE MORNING AND
THEN AGAIN AROUND NOONTIME.
YOU'RE GOING TO SEE IN THESE
INDIVIDUALS LIPOGENESIS BEING
VERY LOW AT MIDNIGHT IN SOME OF
THEM, ALMOST NOTHING UP IN
SUBJECT NUMBER TWO UP THERE,
ALMOST NOT MEASURABLE.
YOU'LL ALSO SEE THE PATTERN RISE
AND IS HIGHER IN MANY
INDIVIDUALS, IT'S HIGHER AFTER
THE SECOND MEAL OF THE DAY,
HIGHER AGAIN AFTER DINNER AND
THEN PEAKING AT NIGHTTIME.
SO HERE ARE THE INSULIN VALUES.
ACROSS THE BOARD, INSULIN IS
HIGHER IN INDIVIDUALS THAT HAVE
JAI AHIGH LIPOGENIC RATES BUT IT
REALLY ISN'T A VERY GOOD
PREDICTOR.
SO LET'S LOOK AT THIS PATHWAY
WHEN IT'S IN THE SETTING OF
OVEREATING.
THIS STUDY IS CALLED THE
TAILGATE STUDY, AS YOU WILL SEE
WHY IN A MINUTE.
WE RECRUITED 18 OVERWEIGHT
SUBJECTS, BMI OF 32, AND THEY
WERE STUDIED ONLY ON ONE
OCCASION.
THIS IS NOT A WELL CONTROLLED
BLINDED STUDY, AS YOU CAN
IMAGINE.
THEY CAME INTO THE CLINICAL
RESEARCH CENTER, THEY HAD AN
MRIMRS TO MEASURE LIVER FAT.
WE PLACED AN I.V. LINE, AND THEN
THE TREATMENT OCCURRED, AND THAT
WAS A TAILGATE WITH ALCOHOL.
AT THE END OF THE DAY, WE PUT
THEM BACK IN THE SCANNER AND
THEN BECAUSE THEY HAD ALCOHOL IN
THEM, THEY SLEPT OVERNIGHT AT
THE CLINICAL RESEARCH CENTER AND
WE DREW BLOOD THE NEXT MORNING
TO SHOW THAT THEY WERE NO LONGER
DRUNK.
THIS IS WHAT WE FED THEM.
THEY WERE ENCOURAGED TO EAT,
THEY WERE WATCHING SPORTS ON TV,
THEY WERE -- WE DID THIS IN
PAIRS, AND WE REFRESHED THE
BUFFET TO MAKE IT ENTICING.
THREE DAYS BEFORE WE STUDIED THE
SUBJECT, THEY CONSUMED HEAVY
WATER TO MEASURE LIPOGENESIS, SO
THIS IS A DEUTERIUM LABELED
WATER, PEOPLE DRINK IT, IT'S
RELATIVELY EASY TO USE, AND WHEN
FATTY ACIDS ARE BEING MADE FROM
SUGARS, THE PATHWAY GETS LABELED
WITH WATER.
SO HERE IS THE SUBJECT
SUBJECTIVE INTOXICATION DATA,
WITH ZERO BEING NOT DRUNK AT ALL
AND 10 BEING MORE DRUNK THAN
I'VE EVER BEEN IN MY LIFE.
AND YOU CAN SEE THESE PEOPLE
WERE HAPPY, THIS WAS NOT A
SLOPPY STUDY.
THESE WERE PEOPLE WHO DRANK
ALCOHOL HABITUALLY.
HERE'S THE BREATH ALCOHOL.
OUR GOAL WAS TO KEEP THEM RIGHT
AT THE LEGAL LIMIT IN MISSOURI
ALL AFTERNOON, AND WE DID
ACHIEVE THAT.
IF THEIR BLOOD ALCOHOL ROSE A
LITTLE TOO HIGH, WE SAID WHY
DON'T YOU WAIT A LITTLE BIT, IF
IT WAS TOO LOW, WE ASKED THEM,
WOULD YOU HAVE ANOTHER DRINK.
THEY WEREN'T REQUIRED TO DRINK,
BUT OUR GOAL WAS TO KEEP THEM IN
THAT TARGET RANGE IF POSSIBLE.
AND THEN I'LL REMIND YOU THEY
HAD THE LIVER MRI BEFORE AND
AFTER, AND WHEN I FIRST SAW
THESE DATA FROM THE GRAD
STUDENT, I WAS DUMBFOUNDED.
I THOUGHT FOR SURE WE WOULD
INCREASE LIVER FAT WITH ALL OF
THAT FOOD AND ALCOHOL.
SO I ASKED HIM TO GO BACK AND
LOOK AT THE INDIVIDUAL DATA, AND
THIS IS A SMALL STUDY, BUT HE
SIMPLY CRUDELY PLOTTED ALL THE
RESULTS ON A GRAPH, AND THE
INDIVIDUALS ON THE LEFT HAD AN
INCREASE IN LIVER FAT AND THOSE
ON THE RIGHT HAD A REDUCTION IN
LIVER FAT.
SO I SAID WELL, WHAT DID THEY
EAT?
WELL, THEY ATE CLOSE TO
5,000-CALORIES ALL AFTERNOON,
AND THIS INCLUDES THE ALCOHOL.
SO WE DIVIDED THIS INTO THE
INDIVIDUALS WHO GAINED LIVER FAT
ON THE LEFT THERE, AND YOU CAN
SEE THEIR ALCOHOL INTAKE WAS
ACTUALLY LESS THAN THE
INDIVIDUALS WHO LOST LIVER FAT,
AND THEY CONSUMED MORE
CARBOHYDRATE ADD LIBITUM.
THIS IS DE NOVO LIPOGENESIS
MEASURED WITH LABELED WATER FROM
NOON TO 5:00 P.M., AND WITHIN
THE TRIGLYCERIDE IN THE BLOOD,
YOU CAN SEE THE SIGNAL COMING
OUT OF THE LIVER, AND THOSE
INDIVIDUALS WHO INCREASED LIVER
FAT DURING OVEREATING TURNED ON
THIS PATHWAY FROM THE SUGARS AND
THE ALCOHOL THEY CONSUMED.
AND THE CHANGE IN LIVER FAT
SYNTHESIS, AS MEASURED BY DE
NOVO LIPOGENESIS, CORRELATED
WITH THE PERCENT CHANGE WITH
MRI.
SO I THINK IT'S REAL.
YOU SEE VARIABILITY THERE.
BUT THOSE INDIVIDUALS THAT
TURNED ON DE NOVO LIPOGENESIS
WHILE OVEREATING WERE THE SAME
INDIVIDUALS THAT GAINED LIVER
FAT.
SO I SHOW THIS DATA BECAUSE THIS
REALLY GOT ME THINKING, I
THOUGHT I KNEW WHAT WAS GOING TO
HAPPEN.
I'VE THOUGHT FOR SURE I WOULD
HAVE GONE TO VEGAS ON THIS, AND
I WAS WRONG.
YOU CAN'T REALLY KNOW SOMEONE'S
SENSITIVITY TO EXCESS FOOD
INTAKE UNTIL YOU DO THE
MEASUREMENTS.
ALL RIGHT.
SO DE NOVO LIPOGENESIS
CONTRIBUTES TO
METABOLIC-ASSOCIATED
STIATOHEPATITIS, SO I WANTED TO
KNOW IF REDUCING IT WAS
SUFFICIENT TO LEAD TO HASH
REGRESSION.
SO THIS CONCEPT, I BRING THIS UP
NOW, I'M NOT GOING TO SHOW YOU
THE REDUCTION DATA YET BUT THIS
IS AN ACTIVE FIELD OF RESEARCH
AND THE REASON IS, BECAUSE FOR
THE MAJORITY OF MY CAREER,
PEOPLE TOLD ME THAT DE NOVO
LIPOGENESIS IS JUST MAKING FAT,
AND THAT IS INERT.
IN THE HEPATOLOGY FIELD, IT'S
CALLED SIMPLE STIATOSIS.
I DON'T THINK IT'S SIMPLE AT
ALL.
I THINK EXCESS FAT IN THE LIVER
IS A BIG FLAG TO THE BODY,
OVERFED, TOO MANY CALORIES,
STRUGGLING WITH ENERGY BALANCE.
AND THAT THOSE FATTY ASITS CAN
BE TOXIC IN THEMSELVES.
WHY DO I THINK THAT THIS IS MORE
THAN JUST FAT SYNTHESIS?
IT'S BECAUSE NEWLY MADE FATTY
ACIDS IN THE LIVER ARE HANDLED
DIFFERENTLY THAN FATTY ACIDS
THAT COME IN FROM OUTSIDE THE
LIVER.
WE KNOW THEY'RE PROCESSED
DIFFERENTLY IN DROPLETS, THEY'RE
USED DIFFERENTLY FOR FAT
OXIDATION.
INCREASED TE DE NOVO LIPOGENESIS
ADDS FATTY ACIDS TO THE
LIPOPARTICLE THAT'S LEAVING.
FRUCTOSE AND -- THEY MAKE THE
PARTICLE BIGGER AND INCREASE
TRIGLYCERIDES IN THE BLOOD.
WHEREAS RESTRICTING DE NOVO
LIPOGENESIS, RESTRICTING SUGARS
REDUCES THE PARTICLE SIZE.
SO DNL ALSO CONTRIBUTES TO
HYPERLIPIDEMIA.
REDUCING FREE FATTY ACID FLUX
FROM THE ADIPOSE TISSUE, WITH
THINGS LIKE INSULIN OR NIACIN,
REDUCES THE PARTICLE NUMBER.
SO FREE FATTY ACIDS COME INTO
THE LIVER AND THEY ARE PROCESSED
DIFFERENTLY THAN THE ONES THAT
ARE MADE LOCALLY.
DE NOVO LIPOGENESIS CONTRIBUTES
PULMITATE, A SATURATED FATTY
ACID, AND SATURATED FATTY ACIDS
IN CELL CULTURE INCREASE
HEPATOCYTE OXIDATIVE STRESS, ER
STRESS, INFLAMMATION, AND
APOPTOSIS.
SUCROSE-DRIVEN DE NOVO
LIPOGENESIS EXACERBATES THE
HEPATIC TOXICITY OF DIETARY
SATURATED FAT.
SO WHEN YOU TURN THIS
BIOCHEMICAL PATHWAY ON, IT IS
GOVERNING THE FATES OF FATTY
ACIDS FROM OTHER SOURCES.
IF I GET UP IN THE MORNING AND
I'M FASTING AND I EAT A PAT OF
BUTTER, I WILL BURN THAT BUTTER.
IF I EAT A PAT OF BUTTER AND EAT
A GENTLEMANLY BEAN WITH IT, I
WILL NOT BURN THE BUTTER.
WHEN YOU TURN ON FATTY ACID
SYNTHESIS, YOU ROUTE OTHER FATTY
ACIDS TO STORAGE AND AWAY FROM
OXIDATION.
THIS HAS BEEN SHOWN IN NUMEROUS
RODENT MODELS AND IN HUMANS.
SO THE QUESTION IS WHAT ELSE IS
CONNECTED TO THIS PATHWAY, AND
WE KNOW THAT MURI IS
THEY'RE ALSO USED TO TARGET
PROTEINS TO VARIOUS LOCATIONS IN
THE CELL AND I HAVE A QUESTION
AS TO WHETHER FATTY ACID
SYNTHESIS, WHEN IT'S TURNED ON,
IS CONTRIBUTING TO CELLULAR
SIGNALING IN THAT MANNER CH SO
IF DE NOVO LIPOGENESIS IS HIGH,
AND THIS IS AN OLD TERM, IN
NON-ALCOHOLIC FATTY LIVER
DISEASE, DOES IT CONTRIBUTE TO
GRADED INCREASES ACROSS THE
SPECTRUM OF DISEASE?
DOES IT ONLY CONTRIBUTE FAT AND
STOPS THERE?
OR DOES IT CONTRIBUTE AS PEOPLE
GET SICKER?
SO MAJID SYED PROPOSED STUDYING
49 PATIENTS HEADED FOR BARIATRIC
SURGERY.
HE GAVE THEM LABELED WATER
BEFORE THE SURGERY AND THEN
WAITED FOR THE SURGEON TO BE
ABLE TO SAMPLE A LITTLE WEDGE
PIECE OF THE LIVER, WHICH WAS
COMMON AT OUR INSTITUTION, TO
MAKE SURE THAT INDIVIDUALS WITH
OBESITY GOING TO BARIATRIC
SURGERY TO DOCUMENT WHAT THEIR
LIVER CONDITIONS WERE.
AND THEN HE TOOK THAT SAMPLE AND
WENT BACK TO THE LAB AND
ANALYZED IT.
HE LOOKED AT THE HISTOLOGY AND
DIVIDED THESE PATIENTS BETWEEN
HAVING NO DISEASE AT ALL,
NON-ALCOHOLIC FATTY LIVER, PORE,
BORDERLINE STEATOHEPATITIS AND
AUTISM OUT STEATOHEPATITIS AND
ANALYZED THE SAMPLES.
SO I'LL SHOW YOU SOME PROOF OF
CONCEPT HERE.
AS ONE LIPID GOES UP, THE OTHER
DOES.
AND THEY'RE BOTH HIGHER IN THE
WORST LIVER CASES.
THIS IS LIVER DE NOVO
LIPOGENESIS AND TRIGLYCERIDE DE
NOVO LIPOJEP CYST.
SO THESE NEW FATTY ACIDS REALLY
DO NOT GO EVERYWHERE.
THEY'RE SELECTIVELY PUT IN
TRIGLYCERIDE.
THIS IS THE FATTY ACID SYNTHASE
PROTEIN THAT'S SUPPOSED TO BE
CARRYING OUT THIS REACTION AND
IT CORRELATES VERY, VERY WELL
WITH THE ACTIVITY THAT'S GOING
ON AS MEASURED BY LABEL.
AND THEN LASTLY THE FRACTIONAL
LIPOGENESIS IN THE LIVER
CORRELATES VERY, VERY NICELY
WITH WHAT'S OUT IN THE BLOOD IN
VLDL.
SO THESE DATA SHOW THAT I DON'T
HAVE TO DO A LIVER BIOPSY TO
FIGURE OUT WHAT'S GOING ON IN
THAT ORGAN.
I CAN LOOK AT THE LIPIDS THAT
ARE BEING SECRETED AND
UNDERSTAND THE CONTROL OF THIS
PATHWAY.
SO IF YOU LOOK AT THEIR LEVELS
OF DISEASE, DE NOVO LIPOGENESIS
INCREASES ACROSS ALL OF THEM.
IT IS NOT DIFFERENT BETWEEN THE
BORDERLINE NASH AND THE NASH,
BUT IT'S DEFINITELY ELEVATED IN
INDIVIDUALS WITH HEPATOCELLULAR
BALLOONING AND INFLAMMATION.
SO I ASKED LET'S LOOK AT IT A
DIFFERENT WAY.
SOME PEOPLE THINK OF THIS
DISEASE AS FIRST STEATOSIS, THEN
INFLAMMATION, AND YOU KEEP
ADDING RISK TO GET TO CIRRHOSIS.
SO HE DIVIDED INTO THOSE WITH A
HEALTHY LIVER, THOSE WITH
STEATOSIS, HE ADDED BALLOONING
AND FIBROSIS AS WELL.
WHAT YOU SEE IS THE PATHWAY IS
INCREASED IN EVERY SUBJECT WHO'S
SICKER AND GOT WORSE LIVER
DISEASE UNTIL YOU GET TO THE
END, AND WE REALLY BELIEVE THAT
THOSE INDIVIDUALS WITH GU FIBRO,
GENERALLY GLOBALLY THEIR LIVER
IS FAILING.
PROTEIN SYNTHESIS IS PROBABLY
AFFECTED, LIPID SYNTHESIS IS
AFFECTED.
SO THAT'S MAKING FAT IN THE
LIVER.
I WANT TO SHOW YOU HOW WE CAN
LACK AT OTHER FATTY ACIDS COMING
INTO THE LIVER GET STORED THERE.
THIS IS CALLED THE INEFA MODEL.
SO NOW WE'RE TALKING ABOUT THE
RIGHT-HAND SIDE, THE LOWER RIGHT
HERE.
WHEN ONE EATS A MEAL, INSULIN
SHOULD TURN OFF FREE FATTY ACID
RELEASED FROM ADIPOSE TISSUE.
IT DOESN'T COMPLETELY TURN IT
OFF.
SOME FATTY ACIDS STILL ARE
COMING OUT OF LIPOLYSIS, AND
ALSO AFTER A MEAL, DIETARY FAT
IN THE CHYLOMICRON IS BEING
BROKEN DOWN AND FATTY ACIDS ARE
BEING TAKEN UP INTO THE ADIPOSE
AND THE MUSCLE.
SO I ASKED THE QUESTION, IF
INSULIN INCREASES GLUCOSE UPTAKE
INTO CELLS, DOES IT ALSO
INCREASE FATTY ACID UPTAKE INTO
CELLS?
THE STORY WITH INSULIN AND
ADIPOSE IS THAT RED CROSS THERE.
IN MY FIELD, YOU LEARN INSULIN
TURNS OFF ADIPOSE LIPOLYSIS, AND
THERE HAS BEEN MUCH, MUCH LESS
FOCUS ON WHAT ELSE IN INSULIN IS
DOING TO LIPIDS.
SO I WENT TO THE LITERATURE, AND
THIS IS A FRACTIONAL CATABOLIC
RATE ON THE Y AXIS.
THIS IS THE SPEED AT WHICH FATTY
ACIDS ARE LEAVING THE PLASMA,
AND THESE DATA WEREN'T EXACTLY
IN EVERY ONE OF THESE PAPERS,
BUT YOU COULD CALCULATE THEM
BASED ON THE DATA PRESENTED.
AND WHEN YOU LOOK ACROSS WHAT'S
IN THE LITERATURE, IT APPEARS
THAT THE HIGHER LEVEL OF
INSULIN, THE GREATER THE UPTAKE
OF FATTY ACIDS INTO CELLS.
SO WE BEGAN TO QUANTIFY INSULIN
MEDIATED NEFA UPTAKE, AND WE DID
TWO RESEARCH TESTS IN A SINGLE
SUBJECT.
THE FIRST WAS AN INTRAVENOUS
GLUCOSE TOLERANCE TEST AND THEN
WE DID A MEAL STUDY AND MEASURED
THE FATTY ACID FLUX USING
ISOTOPES.
THE MEAL WAS LABELED WITH 13C
HEAVY PALMITATE MIXED IN TO
FETTUCINE SAUCE ON PASTA, AND
THEN WE DREW BLOOD ALL NIGHT AND
WE STARTED INFUSING A PALMITATE
LABEL INTO THE BLOOD AT MIDNI
MIDNIGHT.
ALL THOSE TINY LITTLE BLOOD
DRAWS, THIS IS STILL HALF OF AN
AMERICAN RED CROSS BLOOD DRAW.
AT LUNCH WE FED A SECOND MEAL,
WHICH WAS EXACTLY THE SAME MEAL
AS THE FIRST BUT WE PUT A
DIFFERENT ISOTOPE IN SO WE COULD
TRACK LUNCH AS WELL.
SO THIS IS MY SIMPLE SCHEME THAT
BOB FEHR, MY GOOD COLLEAGUE, AND
I DEVELOPED.
ON THE LEFT-HAND SIDE WE'RE JUST
GOING TO CALL THIS SWIM LANE AN
ADIPOSE TISSUE, BECAUSE THAT'S
WHERE MOST OF THE FATTY ACIDS IN
THE BLOOD PLASMA ARE COMING
FROM, AND WE KNOW WELL THAT
INSULIN TURNS OFF THE RELEASE OF
ADIPOSE TISSUE.
YOU'VE GOT VLDL TRIGLYCERIDE AND
ALSO CHYLOMICRON TRIGLYCERIDES
AND WE HYPOTHESIZED THAT INSULIN
WOULD INCREASE THEIR BREAK DOWN
AND SOME OF THOSE FATTY ACIDS
WOULD BE RELEASED RIGHT THERE IN
THE PLASMA AND STAY IN THE
PLASMA.
AND THEN THE LAST PART OF THIS
MODEL IS THAT FATTY ACIDS WOULD
BE TAKEN UP INTO TISSUES,
MUSCLE, KIDNEY, WE CAN'T TELL
WHAT, BUT THEY'RE LEAVING THE
PLASMA AS A RESULT OF INSULIN.
SO JUST BEAR WITH ME.
THIS IS THE MATH THAT'S
UNDERNEATH ALL OF THIS.
IT ALL GOES INTO A LARGE MODEL
TO LOOK AT THE CHANGE OF FREE
FATTY ACID CONCENTRATION IN FLUX
OVER TIME FROM THE FASTING TO
THE FED STATE.
THAT TOP RIGHT BOX UP THERE IS
CALLED SPILLOVER.
THIS IS WHEN DIETARY FATTY ACIDS
THAT ARE IN CHYLOMICRONS END UP
IN THE FREE FATTY ACID POOL.
THEY SHOULD BE TAKEN UP AROUND
THE BODY, BUT LIPOLYSIS CAN
HAPPEN SO FAST IN THE PLASMA
THAT THEY SPILL OVER INTO THE
FREE FATTY ACID POOL.
AND THE ONE ON THE BOTTOM IS
INSULIN MEDIATED UPTAKE.
ALL RIGHT.
SO WE DEVELOPED FROM THIS MODEL
SOMETHING CALLED A KI.
THIS IS THE RATE IN WHICH
INSULIN HALF MAXIMALLY
SUPPRESSES ADIPOSE RELEASE BY
TURNING OFF LIPOLYSIS ENZYMES.
A HIGH NUMBER OR HIGH KI FOR A
PATIENT DENOTES ADIPOSE INSULIN
RESISTANCE.
THAT MEANS THAT YOU HAVE TO PUT
A LOT OF INSULIN INTO THAT
PERSON TO GET THE ADIPOSE TISSUE
TO SHUT UP, RATE, TO TURN OFF.
RIGHT, TO TURN OFF.
THAT'S A HIGH KI.
A HIGH KM IS THE RATE CONSTANT
FOR INSULIN MEDIATED FATTY ACID
UPTAKE, AND THIS AMOUNT IS
NEEDED TO HALF MAXIMALLY
STIMULATE TISSUE UPTAKE.
A HIGH NUMBER DENOTES SKELETAL
MUSCLE INSULIN RESISTANCE.
WE DIDN'T MEASURE PROTEINS AT
THE MUSCLE, BUT THROUGH
TRANSPORTERS LIKE CD36 AND FATTY
ACID TRANSPORT PROTEIN.
AND IN OUR MODEL, THESE TWO
NUMBERS TURNED OUT TO BE ABOUT
THE SAME, WHICH MEANS THAT
INSULIN HAS JUST ABOUT AS MUCH
EFFECT OF CAUSING FATTY ACIDS TO
LEAVE THE BLOOD AND GO INTO
MUSCLE AS IT DOES TO TURN OFF
ADIPOSE RELEASE.
SO A HIGH RATIO DENOTES PEOPLE
MORE INSULIN AND A LOW RATIO
DENOTES MORE INSULIN RESISTANT
AT SKELETAL MUSCLE.
THESE ARE SOME OF THE PATIENTS
THAT WE CALCULATED AND WE LOOKED
AT THEIR WHOLE BODY FAT
OXIDATION.
THERE WERE A NUMBER OF
PHENOTYPIC CHARACTERISTICS THAT
WERE CORRELATED WITH THIS MODEL.
AND ONE WAS THAT THE HIGHER THE
ADIPOSE INSULIN RESISTANCE, THE
GREATER THE FAT OXIDATION AFTER
A MEAL.
AND THE HIGHER THE SKELETAL
MUSCLE INSULIN RESISTANCE, YOU
DIDN'T HAVE GOOD OXIDATION OF
FATTY ACID AFTER A MEAL.
SO THESE ARE WHAT THE DATA LOOK
LIKE.
THIS IS FROM A SINGLE SUBJECT.
THE MODEL WE USE, WE PUT IN ALL
THE CONSTRAINTS WE KNOW FROM THE
LITERATURE.
WHAT IS THE LEVEL OF INSULIN TO
CONTROL LIPOLYSIS ENZYMES, FOR
INSTANCE?
WE GET ALL THAT INFORMATION FROM
THE LITERATURE AND WE PUT IT
INTO A MODEL AND THEN WE SEE
DOES THAT MODEL PREDICT OUR
POINTS THAT WE ACTUALLY
OBSERVED.
IF IT DID, THEN THE ELEMENTS OF
THE MODEL ARE LIKELY GOOD
CONTRIBUTORS FOR FATTY ACID
FLUX.
SO THIS IS MIDNIGHT ON THE LEFT.
THE BLUE MODEL IS THE ONE THAT
INCLUDES AN INSULIN SENSITIVE
UPTAKE OF FATTY ACIDS, A
COMPONENT OF THE MODEL.
WHEN THAT'S LEFT OUT, I CAN'T
REALLY GET THE MODEL TO LINE UP
WITH REALITY, WHICH IS WHAT WE
OBSERVE.
AND THAT'S A SINGLE SUBJECT.
THESE ARE A NUMBER OF SUBJECTS,
16 OF THEM.
YOU CAN SEE THIS IS DURING THE
ORAL GLUCOSE TOLERANCE TEST, WE
WERE ABLE TO PREDICT THE PREFATY
ACID FALL WITH INSULIN, AND THEN
AS THE INSULIN WEARS OFF, YOU
CAN SEE THE FATTY ACIDS COMING
BACK OUT TO BLOOD.
THERE ARE LOTS OF HYPOTHESES
THAT COME FROM THIS KIND OF A
MODEL THAT WE CAN TEST NEXT.
ALL RIGHT.
SO WE TALKED ABOUT LIPOGENESIS
AND WE'VE TALKED ABOUT THE
ADIPOSE TISSUE.
NOW LET'S LOOK AT A CHANGE IN
FAT IN THE LIVER.
I'M GOING TO SHOW YOU DATA FROM
TWO LIFESTYLE TREATMENT STUDIES.
ONE WITH AN INTRAVENOUS GLUCOSE
TOLERANCE TEST, THE OTHER ONE
WITH A HYPERCLAMP AND A TEST
MEAL AND THEN WE ALWAYS USE
IMAGING TO MEASURE LIVER FAT.
SO THE FIRST DIET STUDY WAS DONE
IN NON-DIABETIC SUBJECTS SIX
MONTHS LONG.
THE SECOND ONE IS ONE WE
FINISHED LAST YEAR THAT'S A DIET
AND EXERCISE INTERVENTION IN
DIABETICS AND NON-DIABETICS.
AND THIS IS THE FIRST STUDY
DESIGN.
ON THE LEFT-HAND SIDE YOU'LL SEE
WE CONSENTED THE SUBJECTS, AND
THEN WE DID THE TOLERANCE TEST
AND SOME OTHER STUDIES I WOULD
ANY TIME SHOW YOU "TODAY"
SHOWING GLUCOSE AND KETONE
PRODUCTION, AND THEN THEY CAME
BACK THE AND DID A LIPID STUDY.
SO THE BOTTOM IS THE FORMAT OF
THE INPATIENT LID IP STUDY.
WE'RE USING LABELED WATER TO
MEASURE LIPOGENESIS.
THE PERSON COMES IN, THEY GET AN
EVENING MEAL.
WE'RE MEASURING VLDL SYNTHETIC
RATE, WE GAVE THEM THE LUNCH AS
I SHOWED YOU BEFORE, AND A
COUPLE OF THESE SUBJECTS WERE
HEADING FOR THEIR DIAGNOSTIC
LIVER BIOPSY, AND SO THEY WERE
KEPT IN THE UNIT IF THEY WERE
HEADING FOR MEDICAL CARE THE
NEXT DAY.
ALL RIGHT.
SO WHAT DID THE WEIGHT LOSS DO?
10% WAS OUR GOAL AND THAT'S WHAT
WE ACHIEVED.
INSULIN SENSITIVITY INCREASED
WITH WEIGHT LOSS.
YOU DON'T ALWAYS SEE THIS, BUT
IN THIS CASE, WE GOT A
SIGNIFICANT IMPROVEMENT.
LIVER TRIGLYCERIDE DROPPED
SIGNIFICANTLY DOWN THERE.
LOOK HOW LOW THAT IS, 3.5%.
AND LASTLY, ALT BECAME
NORMALIZED AFTER WEIGHT LOSS.
SO THIS IS THE WEIGHT LOSS
CURVES, AND THIS DIETITIAN WAS
ABSOLUTELY AMAZING.
SOMETIMES WE SEE WEIGHT LOSS
COME DOWN AND THEN WE'LL SEE
PEOPLE REGAIN, AND YOU'LL ALSO
SEE THE VARIABILITY IN THESE
CURVES.
HALF OF THESE PEOPLE HAD LOW
LIVER FAT FOR STARTERS AND THE
OTHER HALF HAD HIGH, AND WE
WANTED TO COMPARE THE RESPONSE
OF ENERGY RESTRICTION IN THIS
SETTING.
THIS IS WHAT WEIGHT LOSS DID TO
LIVER FAT.
YOUR LOW LIVER FAT PEOPLE ARE
THERE ON THE BOTTOM.
INDIVIDUALS WHO STARTED WITH
HIGH LIVER FAT CAME DOWN AND A
COUPLE OF THEM ACTUALLY DID NOT
ACHIEVE NORMALIZATION OF THEIR
LIVER FAT EVEN AFTER LOSING 10%
BODY WEIGHT.
THERE WAS A MAIN EFFECT OF
WEIGHT LOSS IN GENERAL FOR
EVERYONE.
SO THO THESE ARE THE POSTPRANDI-
WHAT IS SOMEONE DOING WHEN THEY
LOSE WEIGHT TA LEADS TO LIVER
HEALTH.
THERE WERE NO DIABETICS HERE,
THIS WAS A 10% WEIGHT LOSS.
THE OPEN SYMBOLICS ARE BASELINE
AND THE FILLED ARE FOLLOW-UP AND
GLUCOSE DIDN'T CHANGE.
THIS IS THE FREE FATTY ACID CON
ACCCONCENTRATIONS.
AGAIN, WE'RE STARTING AT
6:00 P.M. FEEDING DINNER, THE
EVENING MEAL, AND ZERO IS
MIDNIGHT.
AND YOU CAN SEE INSULIN IS
SUPPRESSING FREE FATTY ACID
CONCENTRATION IN THE BLOOD.
YOU CAN SEE IT COME BACK AND
VERY REACTIVE AFTER WEIGHT LOSS.
YOU DON'T GET THIS SPIKE OF FREE
FATTY ACIDS.
THE OTHER THING THAT HAPPENED IS
WITH FASTING, THERE IS A RISE
TOWARD DAWN IN FREE FATTY ACIDS
IN MOST PATIENTS WHO STRUGGLE
WITH OBESITY.
THAT RISE RIGHT UP TO LUNCH WAS
MISSING AFTERWARDS.
AND WE HAD BASICALLY BEEN
STARVING THEM FOR SIX MONTHS.
I THINK THEY GOT MUCH BETTER AT
FASTING.
AND THEN AFTER THE SECOND MEAL,
THE LUNCH, YOU SEE THIS REALLY
GREAT SUPPRESSION OF ADIPOSE
TISSUE FATTY ACIDS.
THIS IS THE INSULIN LEVELS.
YOU SOMETIMES WON'T SEE A CHANGE
IN GLUCOSE, BUT BOY, DO YOU SEE
A SUPPRESSION IN THE AMOUNT OF
INSULIN NEEDED.
AND THEN LASTLY, MY OUT COME OF
INTEREST ARE TRIGLYCERIDES.
AND THE TRIGLYCERIDES OCCUR IN
THE OPEN SYMBOL, THE
TRIGLYCERIDES OCCURRING LATE AT
NIGHT ARE REALLY RISING
THROUGHOUT THE DAY.
FOR MOST PEOPLE, OUR
TRIGLYCERIDES RISE AFTER
BREAKFAST, THEY RISE AGAIN AFTER
LUNCH, AND THEY PEAK AFTER
DINNER.
AS I'VE SAID IN THE MIDDLE OF
THE NIGHT, WHEN WE'RE SLEEPING.
AND THAT PEAK WAS DAMPENED
EXTREMELY, AND EVEN THE LUNCH
RISE IS LOWER AFTER WEIGHT LOSS.
SO THIS IS TO REMIND ME THAT I
LABELED ALL THESE THREE SOURCES.
THE DIET, DE NOVO LIPOGENESIS,
AND ADIPOSE TISSUE.
NOW I'M GOING TO PUT THEM
TOGETHER FOR YOU.
SO THIS IS THE CONTRIBUTION OF
DINNER TO LIVER FAT REA PSYCHED
BACK THROUGH VLDL.
THERE'S NOT A REALLY BIG CHANGE
THERE.
THOSE INDIVIDUALS WITH HIGH
LIVER FAT AT BASELINE ACTUALLY
HAD AN INCREASE IN THIS
PARAMETER AFTER WEIGHT LOSS.
THIS IS WHAT THE FREE FATTY ACID
RECYCLING THROUGH THE LIVER
LOOKS LIKE.
IT'S RISING FROM MIDNIGHT, AND
FREE FATTY ACIDS ARE BEING USED
MORE FOR TRIGLYCERIDE SECRETION
AFTER WEIGHT LOSS.
THEY'RE COMING FROM THE ADIPOSE,
THEY GET PACKAGED, THEY'RE PUT
IN VLDL AND THEY'RE SENT BACK
OUT TO THE BODY.
AND LASTLY, THIS IS DE NOVO
LIPOGENESIS.
WHAT YOU SEE IS THAT IT IS DOWN
BY HALF.
IT IS THE OUTCOME THAT CHANGED
MOST IN THESE PATIENTS, AND WE
HAVE CLOSE TO 200 PHENOTYPES IN
ALL THE HORMONES, CONCENTRATIONS
OF EVERYTHING, BODY COMPOSITION,
EVERYTHING.
THIS IS THE ONE FACTOR THAT
PREDICTED LOSS OF LIVER FAT, WAS
THE SUPPRESSION OF THIS PATHWAY.
NOW WHAT YOU DO SEE IS THAT THE
INDIVIDUALS WHO STARTED WITH LOW
LIVER FAT, THEIR LIPOGENESIS IS
DOWN BELOW 5%, AND IT SUPPRESSES
VERY QUICKLY.
THE INDIVIDUALS THAT STARTED
WITH HIGH LIVER FAT STILL HAVE
THIS KIND OF SU CIRCADIAN
DISRUPTION IN THE PATHWAY AND IT
STAYS HIGH ALMOST ALL NIGHT.
AND THAT PERSISTED AFTER WEIGHT
LOSS.
SO IF YOU LOOK IN VLDL IN THE
FASTING STATE, THIS IS WHAT YOU
SEE.
PEOPLE WITH LOW LIVER FAT ARE ON
THE LEFT-HAND SIDE AND HIGH ON
THE RIGHT.
THESE ARE THE PROPORTIONS OF THE
VARIOUS SOURCES THAT THE LIVER
MACHINERY IS DEALING WITH, AND
CHOOSING HOW TO STERIFY THEM.
YOU SEE THE MAJORITY IS COMING
FROM THE FATTY ACID POOL.
LIPOGENESIS IS SIGNIFICANTLY
HIGHER IN THE INDIVIDUALS WITH
FATTY LIVER.
AFTER WEIGHT LOSS, LAY POE
GENESIS COMES DOWN IN PEOPLE
WITH LOW LIVER FAT, BUT THERE
REALLY AREN'T ANY OTHER CHANGES.
WHERE AFTER WEIGHT LOSS IN
INDIVIDUALS WITH FATTY LIVER
DISEASE, WE ESSENTIALLY
NORMALIZE THE PROCESSING OF
FATTY ACIDS, AND THE ONLY
VARIABLE THAT PREDICTED THIS WAS
A REDUCTION IN DE NOVO
LIPOGENESIS.
TO LOOK AT IT ANOTHER WAY, IF
YOU LIKE CYCLES, DIET IS UP
THERE ON THE LEFT-HAND SIDE.
IT'S SPILLING OVER ITS FATTY
ACIDS INTO THE FREE FATTY ACID
POOL AND THOSE ARE COMING INTO
THE LIVER, AND THERE WAS NO
CHANGE IN THAT CIRCLE ON THE
RIGHT IN THE GREEN, IN THE
DIETARY CONTRIBUTION TO LIVER
FAT.
ADIPOSE FREE FATTY ACIDS, THEY
WERE 6 IT%, THEY WERE REDUCED
62%, AND DE NOVO LIPOGENESIS WAS
REDUCED 42%.
AND WHEN YOU ADD THOSE TOGETHER,
YOU GET A 66% REDUCTION IN LIVER
FAT BY THE MODEL, WHICH ALSO
CORRELATED WITH IMAGING.
FROM MRS.
ALL RIGHT.
I'LL QUICKLY END HERE WITH DIET
PLUS EXERCISE.
SO NOW WE'RE REALLY GOING TO
FOCUS ON WE'VE REDUCED FOOD
INTAKE, WHICH SHOULD MAKE
MATTERS BETTER IN THE LIVER.
I ALSO THEN WANT TO SEND
CALORIES OVER TO THE MUSCLE.
THAT WAS OUR HYPOTHESIS HERE,
COULD WE PROTECT THE LIVER BY
REROUTING ENERGY AWAY FROM IT.
I WAS COLLABORATOR ON THIS STUDY
WITH SCOTT RICHTER AND ABDUL AT
UNIVERSITY OF MISSOURI.
MOST OF NEW THIS ROOM KNOW HOW
MUCH WORK IT TAKES TO GELTS
THGET THESESTUDIES DONE.
WE RECRUIT THROUGH THE LIVER
CLINIC, WE HAVE AN INPATIENT
UNIT AND OUR IMAGING SUITE IS
REALLY GREAT.
THIS TIME WE RECRUITED PATIENTS
ONLY FROM THE LIVER CLINIC, SO
THESE WERE INDIVIDUALS WITH
DOCUMENTED LIVER DISEASE BY
HISTOLOGY.
WE DID BASELINE TESTS AND
EXERCISE TREADMILL DEX, WE DID
DEXA AND IMAGING AND THEY WERE
RANDOMIZED EITHER TO CONTROL
WHICH WAS FOLLOWING THE CARE OF
THEIR PHYSICIAN OR ENERGY
RESTRICTION AND HIGH INTENSITY
INTERVAL TRAINING.
AND THEN AFTER NINE MONTHS OF
HARD LABOR, WE FOLLOWED UP ALL
THOSE TESTS AND THESE
INDIVIDUALS ELECTED FOR A
FOLLOW-UP LIVER BIOPSY.
IF YOU ASK THEM AT THE BEGINNING
WHY THEY WOULD DO THE STUDY OR
WOULDN'T DO THE STUDY, IT WAS
NOT THE FOLLOW-UP LIVER BIOPSY
THAT KEPT THEM FROM DOING THE
STUDY.
THEY ALL HAD HAD ONE, THEY KNEW
WHAT THEY WERE SIGNING UP FOR.
THEY COULD DECIDE LATER TO NOT
DO IT, THAT WAS FINE, BUT WE
DIDN'T HAVE A SINGLE SUBJECT WHO
DIDN'T WANT TO KNOW WHERE THEY
WERE WITH THEIR DISEASE AFTER
NINE MONTHS.
IF I HAD TO ASK YOU WAS IT THE
EXERCISE OR THE DIET THAT MADE
PEOPLE THE MOST SCARED, WHAT
WOULD YOU SAY, THAT THEY DIDN'T
WANT TO DO THE STUDY BECAUSE OF
ONE OF THOSE, WHAT WOULD IT BE?
>> EXERCISE.
>> IT WASN'T, IT WAS THE DIET.
AND THAT'S BECAUSE WHEN YOU
EXERCISE WITH A COACH, AND WE
HAD GRAD STUDENTS AS COACHES,
THERE'S SOMEONE THERE THREE
TIMES A WEEK, YOU'RE ON THE
TREADMILL, IT'S 20 MINUTES OF
HIT TRAINING, YOU CHECK IT OFF,
YOU GO HOME AND YOU FEEL VERY
VIRTUE U YOU DID YOUR STUDY
WORK.
WHEREAS YOU AND I KNOW THAT A
DIET IS CHALLENGING.
EVERY MINUTE OF THE DAY, YOU'RE
BY YOURSELF, YOU'RE IN THE
GROCERY STORE, AND OUR DIETITIAN
FIELDED CALLS FROM ALL OVER TO
TRY AND SUPPORT THESE SUBJECTS.
THEY KNEW THAT CHANGING THEIR
DIET WOULD BE MORE DIFFICULT.
SO WHO ARE THEY?
HERE THEY WERE.
IT'S A SMALL GROUP.
THEY WERE 75% WERE DIABETIC IN
THE CONTROL AND 63% IN THE
INTERVENTION.
THIS IS -- THEY WERE HIGHLY
SEDENTARY.
IF YOU LOOK AT THE VO2 MAX ON
THE BOTTOM, SOME OF THESE
INDIVIDUALS HAD NEVER EXERCISED
OUTSIDE OF THEIR GRADE SCHOOL
GYM CLASS.
WEIGHT LOSS LOOKED LIKE THIS,
AND THIS IS WHAT WE EXPECTED
WOULD HAPPEN.
SOME INDIVIDUALS IN THE CONTROL
GROUP WOULD LOSE WEIGHT, AND
THAT'S BECAUSE THEY HAD JUST
BEEN DIAGNOSED WITH SIGNIFICANT
LIVER DISEASE.
THEY HAD BEEN TOLD, YOU HAVE
FATTY LIVER WITH A GRADE OF 4 OR
GREATER.
AND THEN ON THE RIGHT-HAND SIDE,
YOU SEE SOME OF THE INDIVIDUALS
IN THE DIET AND EXERCISE GROUP
DID NOT LOSE WEIGHT AT ALL, SOME
LOST WEIGHT AND GAINED IT BACK.
I WANT TO SHOW YOU OR HAVE YOU
LISTEN TO SOME WORDS FROM ONE OF
THE PATIENTS.
>> WHEN I WOULD COME HOME FROM
WORK, I WOULD HAVE TO TAKE A
NAP, I WOULD NOT DO MUCH BECAUSE
I'D BE TIRED JUST WALKING,
GETTING IN AND OUT OF THE CAR
WOULD WEAR ME OUT.
MY PRIMARY CARE DOCTOR RAN TESTS
AND I GOT DIAGNOSED FOR HAVING
FATTY LIVER DISEASE, AND I
DIDN'T REALIZE FATTY LIVER
DISEASE COULD BE FATAL IF I
DIDN'T TAKE CARE OF IT.
I WANT TO BE AROUND FOR MY KIDS,
EVEN THOUGH THEY'RE GROWN NOW,
THEY STILL NEED ME.
I NEED THEM.
THIS PAST NINE MONTHS, I'VE LOST
40 POUNDS.
I FEEL MUCH BETTER.
I USED TO BE ON SOME MEDICATION,
AND NOW I DON'T HAVE TO TAKE
THOSE MEDICATIONS ANYMORE.
I THINK IT'S GREAT THAT MIZZOU
IS DOING THIS RESEARCH AND
HELPING PEOPLE.
I'M PROUD TO BE A PART OF THAT.
>> SO SHE WAS QUITE SUCCESSFUL.
THIS IS THE CHANGE IN LIVER
HISTOLOGY, AND I'LL SHOW YOU HER
DATA IN A LITTLE BIT.
YOU CAN SEE STANDARD OF CARE OF
A COUPLE OF THE SUBJECTS GOT
WORSE OVER NINE MONTHS.
ONE GOT BETTER.
THIS IS THE TREATMENT GROUP, AND
FERN STARTED AT A 5 AND ENDED AT
A ZERO.
SO THIS IS COMPLETE REGRESSION.
WE HAD A WOMAN WHO WENT FROM A
SCORE OF 6 TO 0.
8 IS CIRRHOSIS.
SO YOU WANT TO BE DOWN A LOWER
NUMBER.
THESE ARE THE STEATOSIS SCORES
WITH THE TREATMENT GROUP
SIGNIFICANTLY LOWERING LIVER
FAT.
HERE'S LOBULAR INFLAMMATION,
DOWN.
AND THERE'S HEPATOCELLULAR
BALLOONING AND WE'LL LOOK AT
THAT IN A SECOND.
THAT'S WHEN THE CELLS ACTUALLY
DIE AND THEY LOOK HOLLOW WITH A
LITTLE BIT OF CELLULAR DEBRIS IN
THE MIDDLE.
THAT WAS SIGNIFICANTLY DOWN.
AND THEN HERE IS FIBROSIS.
IT WAS A SIGNIFICANT INTERACTION
BETWEEN THE CHANGES IN THE TWO
GROUPS.
SO WHAT DID THE HISTOLOGY LOOK
LIKE?
SO IN THE UPPER LEFT-HAND SIDE,
THIS IS -- I KNOW YOU CAN'T SEE
THIS VERY WELL.
THIS IS A GRADE OF 7 OUT OF 8.
THE DROPLETS, THE LITTLE WHITE
DOTS YOU'RE SEEING ARE ALL FAT
IN THE LIVER.
THE VERY DARK BLUE DOTS ARE
IMMUNE CELLS AS WELL.
AND THEN AT FOLLOW-UP, THIS
PERSON HAD A SCORE OF 7, THE
PERSON ON THE BOTTOM WENT FROM A
6 TO A 5.
HERE'S THE TREATMENT GROUPS.
THESE ARE TWO -- THERE'S OUR
STELLAR EXAMPLE OF A WOMAN WHO
WENT FROM 7, AND YOU'RE SEEING
DEAD CELLS, LOTS OF HOLES
BASICALLY IN THE TISSUE.
AND THEN ON THE RIGHT, ONE
PATHOLOGIST TOLD ME THAT'S THE
HISTOLOGY OF WHAT LOOKS LIKE A
COLLEGE ATHLETE.
THAT'S A NORMAL, HEALTHY LIVER
THERE ON THE RIGHT.
THE PERSON ON THE BOTTOM WENT
FROM A 6 TO A 2.
HERE ARE FERN'S RESULTS WHICH I
SHARE WITH YOU WITH HER
PERMISSION.
SHE STARTED WITH MACRO AND MICRO
VEST PARTICULAR STEATOSIS WITH
HEPATOCELLULAR BALLOONING AND
DEGENERATION OF THE CELLS.
HER STEATOHEPATITIS WAS THERE
AND SHE HAD EARLY BRIDGING
FIBROSIS FROM ACROSS THE LOBULE.
SHE LOST WEIGHT.
HER LIVER FAT WENT TO 2.5%.
HER PLASMA ALT CAME DOWN.
HER NASH SCORE DROPPED.
HER GLUCOSE DISPOSAL WENT UP AS
A RESULT OF ALL THAT EX-ARE
SEISE AND HER TRIGLYCERIDES
DROPPED.
AFTERWARDS, THIS HIS TOLL GIST
WHO WAS BLINDED DESCRIBED A
SIGNIFICANT REDUCTION IN
STEATOSIS, INFLAMMATION, HE PO
TOE CELLULAR DEGENERATION WAS
SIGNIFICANTLY LOWER.
YOU'RE GOING TO SEE A CRACK IN
THE TISSUE THERE.
THAT HAPPENS DURING THE
HISTOLOGICAL PREP BUT YOU SEE
MUCH LESS DROPLETS THERE, AND
WHEN YOU BLOW THIS UP UNDER THE
MICROSCOPE, YOU CAN SEE THAT THE
TISSUE IS MUCH MORE INTACT.
SO I'M GOING TO SHOW YOU A FEW
PHYSICAL RELATIONSHIPS BETWEEN
THE OUTCOME VARIABLES.
THIS IS THE WEIGHT CHANGE WITH
THE BLUE BEING THE TREATMENT AND
DE NOVO LIPOGENESIS DROPPING ON
THE Y AXIS.
THIS IS DE NOVO LIPOGENESIS AND
LIVER FAT BY MRI.
HERE IS THE ACTIVITY SCORE,
AGAIN THE LOWER THE BETTER, AND
CARDIORESPIRATORY FITNESS.
SO AS INDIVIDUALS INCREASE THEIR
FITNESS ON THE RIGHT, THAT WAS
ASSOCIATED WITH IMPROVEMENT IN
LIVER DISEASE, EVEN IF YOU TAKE
THAT UNBELIEVABLE PERSON THERE
OUT ON THE RIGHT, THERE'S STILL
A SIGNIFICANT RELATIONSHIP
THERE.
AND THEN LASTLY, A CHANGE IN
LIVER FAT WITH A CHANGE IN
HEPATIC GLUCOSE PRODUCTION.
SO WHAT IS THIS?
I CALL THIS THE REROUTE
HYPOTHESIS.
THIS IS ELIMINATING NUTRIENT
OVERLOAD.
IT STARTS WITH ENERGY
RESTRICTION, REDUCTION IN BODY
WEIGHT AND INCREASE IN PHYSICAL
ACTIVITY.
THAT IN MY VIEW, AND WE HAVE THE
TISSUE TO TEST THESE GENE
EXPRESSION, YOU REDUCE
TRANSCRIPTION FACTORS THAT
CONTROL LIPOGENESIS.
YOU REDUCE THE SUBSTRATES TO
MAKE FATTY ACIDS BECAUSE PEOPLE
ARE EATING LESS FOOD AND LESS
CARBOHYDRATE.
FITNESS CAUSED A REDUCTION IN
OUR THEORY OF NUTRIENT OVERLOAD
ON THE LIVER.
THIS REDUCES LIVER FAT AND CELL
DEATH.
IT LOWERS HEPATIC GLUCOSE
PRODUCTION, AND THEN WE SAW
REMISSION OF NASH AND
PREDIABETES AND DIABETES IN THIS
POPULATION.
SO I JUST GOT A BUNCH OF PAPERS
TO SHOW YOU THIS HISTORICAL
ROUTE.
WE STARTED BY DEFINING SUGAR
STIMULATION OF LIPOGENESIS IN
HEALTHY INDIVIDUALS.
PEOPLE THOUGHT LIPOGENESIS WAS
ZERO IN HUMANS.
AND MY ENTIRE POSTDOC, I DID IN
FASTED INDIVIDUALS.
THEY WERE FASTED FOR 20 HOURS
AND THEN I MEASURED LIPOGENESIS.
AND IT WAS VERY LOW.
IT TURNS OUT WHEN YOU BEGIN TO
EAT, IT TURNS ON.
THEN WE DISCOVER THAT
LIPOGENESIS WAS ELEVATED IN
PATIENTS WITH LIVER DISEASE.
AND THEN WE ALSO SHOW THAT IT
HAD LOST ITS CIRCADIAN RHYTHM.
WE'VE TESTED M MITOCHONDRIA FROM
THE LIVERS OF INDIVIDUALS WHO
BEFORE AND AFTER WEIGHT LOSS AND
WE'VE QUANTIFIED THE
MITOCHONDRIAL ACTIVITY AND SHOWN
THAT IT IS IMPROVED WITH WEIGHT
LOSS AND EXERCISE.
I SHOWED YOU THE INIFA MODEL,
AND WE HAVE SPENT A LOT OF TIME
MO MODELING DIETARY FATTEN TRI D
REMOVAL FROM BLOOD.
WE PERFORMED PHARMACEUTICAL
STUDIES SO SHOW THAT REDUCTIONS
IN LIPOGENESIS WITH MEDICATION
LOWERS LIVER FAT, AND THEN WE'VE
ALSO COLLABORATED WITH PEOPLE
HERE AT THE NIH STUDYING SPECIAL
POPULATIONS, WE'VE DONE STUDIES
IN ISOTOPES IN WOMEN WHO ARE
LACTATING AND THEN GENETIC
CAUSES OF FATTY LIVER.
SO IN SUMMARY, LIPOGENESIS
STIMULATED BY DIETARY SUGAR, AND
IN PARTICULAR LIQUID SUGAR
INTAKE AS OPPOSED TO RICE OR
BEANS.
COOL LKOOL-AID IS A LOT WORSE TN
SOLID CARBS.
SUGARS IN ALCOHOL STILL WERE THE
DRIVING FORCE IN THAT STUDY.
THE INDIVIDUALS WHO HAD THE
GREATEST LIPOGENESIS, IT WASN'T
THAT THEY CONSUMED THE MOST
ALCOHOL.
IT WAS SUGAR INTAKE.
ABOVE ALL ELSE, METABOLICALLY
ASSOCIATED STEE A TOE HEPATITIS
IS DISTINCTLY CHARACTERIZED BY
AN UPREGULATION IN THIS
BIOCHEMICAL PATHWAY.
AND IT'S LOST ITS CIRCADIAN
RHYTHM.
IT SHOULD BE SUPPRESSED AT NIGHT
AND DURING FASTING, AND THE
SUPPRESSION IS MISSING IN
PATIENTS.
IT'S AS IF THEIR LEVELS IN THE
FASTING STATE ARE VERY HIGH AND
THEY DON'T GET BETTER.
THERE'S A CEILING.
THEY DON'T GET HIGHER THAN ABOUT
40 TO 50%.
THEY NEVER GO UP BUT THEY ALSO
DON'T GO DOWN.
HIGH LEVELS OF DE NOVO
LIPOGENESIS ARE ASSOCIATED WITH
HIGHER LEVELS OF LIVER DISEASE.
REMOVING TO TOXICITY IN THE LIVR
CAN RESOLVE THIS.
AND I WANT TO END BY EMPHASIZING
THE IDEA OF MEASURING FLUX.
THAT'S OUR LAB MOTTO AND MY
UNDERGRADS MAKE SURE I SAY THAT
EVERY TIME.
WE WOULD HAVE NO DATA IF A
PERSON DIDN'T RAISE THEIR HAND
TO BE IN OUR STUDIES, AND MOST
APPRECIATION GOES TO THEM.
OUR FUNDING, THESE ARE THE
INDIVIDUALS IN MY LABORATORY WHO
HAVE GENERATED THE DATA.
THE 51 STUDENTS WHO COME IN --
HAVE COME IN OVER THE YEARS, AND
ONE ASKED ME ONCE IF I WAS GOING
TO WIN THE NOBEL PRIZE.
YOU KNOW, THEY GET TURNED ONTO
SCIENCE AND THEY REALIZE WHAT
YOU'RE DOING.
AND THEN THINGS GET REALLY,
REALLY FUN.
STAFF, AND THEN THESE ARE THE
UNIVERSITY OF MISSOURI
COLLABORATORS.
STATISTICIANS, HEPATOLOGISTS, WE
REALLY DO THIS ALL TOGETHER.
AND THEN THE COLLABORATORS FROM
OTHER PLACES, U.T. SOUTHWESTERN
MEDICAL CENTER AND THE NIH
OKLAHOMA HEALTH SCIENCES, AND
THE UNIVERSITY OF COLORADO.
I'LL STOP THERE.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU VERY MUCH FOR A
FANTASTIC TALK.
FOR THOSE WHO ARE IN THE ROOM,
IF YOU HAVE QUESTIONS, PLEASE
COME UP TO THE MICROPHONE, AND
THEN IS DR. PARIK HERE
MONITORING -- OKAY, THANK YOU.
SO LET US KNOW.
IS SOMEBODY COMING UP WITH A
QUESTION?
>> I HAVE A QUESTION.
YOU SAID IN YOUR PEN ULTIMATE
SLIDE THAT SENSITIVE INDIVIDUALS
HAVE MORE SUGAR SENSITIVITY TO
FAT DEPOSITION.
I KIND OF MISSED, SENSITIVE IS
CHARACTERIZED BY YOUR RATIO, KI
OVER KM?
OR HOW ARE YOU CHARACTERIZING
THAT SENSITIVITY?
>> I'VE SHOWN ABOUT FOUR
DIFFERENT WAYS -- SO I WASN'T
SPECIFIC WHEN I USED THAT TERM.
SENSITIVE CAN BE THAT THEY TURN
ON LIPOGENESIS VERY QUICKLY, OR
THAT THEY NEVER TURN IT OFF.
IT COULD BE BOTH OF THOSE
THINGS.
WE KNOW THAT IN THE LIVER,
INSULIN SHOULD TURN OFF GLUCOSE
PRODUCTION AND TURN ON
LIPOGENESIS, AND INDIVIDUALS
APPEAR TO BE INSULIN RESISTANT
IN THE GLUCOSE SIDE OF THAT,
THEY KEEP PUTTING GLUCOSE OUT,
BUT THEY'RE SENSITIVE WITH
RESPECT TO FATTY ACID SYNTHESIS,
SO THERE'S THIS DICHOTOMY IN
SENSITIVITY IN THE LIVER.
>> GREAT, THANKS.
>> THAT WAS REALLY WONDERFUL.
THANK YOU SO MUCH.
SO CLEAR.
>> THANK YOU.
>> AND SO MY QUESTION, YOU KNOW
I'M INTERESTED IN THE POST
WEIGHT REDUCED STATE.
YOU'VE RECOVERED SOME OF THAT
METABOLIC FLEXIBILITY, YOU'VE
GOTTEN RID OF SOME OF THE FAT,
YOU SUPPRESSED THE DE NOVO
LIPOGENESIS WHEN THE CALORIE
INTAKE IS LOW.
SO ON THE BACKGROUND OF THAT,
THESE PATIENTS ARE SO IMPROVED
THEN WHAT HAPPENS IF THEY DO
REBOUND WITH THEIR EATING?
ESPECIALLY IN THIS ERA NOW WHERE
PEOPLE ARE TAKING ALL THESE
DRUGS TO SUPPRESS THEIR FOOD
INTAKE, WHAT HAPPENS THEN IF
THEY GO OFF THE DRUG?
>> NO ONE HAS -- THE QUESTION IS
ABOUT THE REBOUND IN BODY WEIGHT
THAT CAN OCCUR.
NO ONE TO MY KNOWLEDGE HAS
MEASURED LIPOGENESIS AFTER
WEIGHT REGAIN.
I THINK OF LIPOGENESIS AS ECK
QIS ITALY SENSITIVE TO RECENT
FOOD INTAKE.
SO MY SENSE WOULD BE, THE MINUTE
THAT BODY WEIGHT START TO COME
BACK UP, THAT MEANS CALORIC
INTAKE IS UP, FATTY LIVER COMES
BACK, LIPOGENESIS WILL COME
BACK.
BUT WE'VE FOUND THAT THIS
PATHWAY DRIVES LIVER FAT ACCRUAL
REGARDLESS OF AGE, IT'S BEEN
SHOWN IN CHILDREN, SEX, RACE AND
ETHNICITY, IN INDIVIDUALS WHO
HAVE EXCESS LIVER FAT, THE
PATHWAY IS ON.
SO IT SEEMS TO BE VERY, VERY
SENSITIVE TO EXCESS ENERGY.
RIGHT THERE.
SO MY PREDICTION WOULD BE THAT
IT WOULD COME BACK EASILY.
WHEN YOU THINK ABOUT IT, THE
INDIVIDUALS WHO LOST 10% OF
THEIR BODY WEIGHT, THEY ARE
STILL IN THE OVERWEIGHT OBESE
CATEGORY.
SO IT'S THAT SET OF FOOD INTAKE
THAT'S REDUCING LIPOGENESIS.
THEY ALSO PROBABLY TOOK 10 TO 15
YEARS TO GET LIVER DISEASE, AN
TO SEE A BIOPSY SHOW LACK OF ANY
DISEASE NINE MONTHS LATER IS
ASTOUNDING TO ME.
AND WE'VE EVEN TALKED IN THE LAB
ABOUT WHETHER OR NOT THERE WOULD
BE A MEMORY, JUST AS INSULIN
TREATMENT EARLY IN DIABETES HAS
A MEMORY THAT IF WE CAN IMPROVE
THE LIVER, WILL IT TAKE AS MUCH
TIME TO GET BACK TO THE SAME
DISEASE STATE?
WILL IT TAKE LONGER?
HOW LONG WILL THESE BENEFITS
LAST?
AND SO I THINK ALTHOUGH
LIPOGENESIS ITSELF IS REALLY
SENSITIVE TO IMMEDIATE INTAKE,
ALL THE OTHER BENEFITS THEY DID
FOR NINE MONTHS ARE GOING TO
LAST LONGER.
>> WELL, AND THERE'S ALL THIS
INTEREST NOW IN INTERMITTENT
FASTING.
>> LIPOGENESIS HAS NOT BEEN
MEASURED IN INTERMITTENT
FASTING, AND OF COURSE MY
PREDICTION WOULD BE THAT
PERIODS, LONGER PERIODS OF
FASTING WOULD REDUCE THE
PATHWAY.
>> DO WE HAVE ANY QUESTIONS THAT
HAVE BEEN POSTED THROUGH THE
WEBSITE?
NOTHING YET?
OKAY.
I'M GOING TO TAKE ADVANTAGE OF
BEING HERE TO ASK YOU A
QUESTION.
SO I HAVE A STRONG INTEREST IN
THE EFFECTS OF INSULIN ON LIPID
METABOLISM, AND I WAS VERY
EXCITED TO SEE YOUR INEFA DATA.
I'M WONDERING IF YOU CAN
SPECULATE ON THE MECHANISMS BY
WHICH INSULIN IS INCREASING
FATTY ACID UPTAKE BY THE MUSCLE.
>> THERE HAVE BEEN A NUMBER OF
STUDIES, CLAMP STUDY WITH MUSCLE
BIOPSY THAT SAYS CD36 IS
CONTROLLED BY INSULIN SO THE
FATTY ACID TRANSPORTER ARE
INCREASED WITH INSULIN ACUTELY
WITH MEALS.
ALL THE TRIGLYCERIDE
SYNTHESIZING ENZYMES, ALL OF
THOSE ARE STIMULATED BY INSULIN
AS WELL, SO I THINK FOR ME, WE
KNOW A LOT ABOUT INSULIN
RESISTANCE TO GLUCOSE AT THE
MUSCLE.
I'M INTERESTED IN INSULIN
RESISTANCE TO FATTY ACID UPTAKE
AT THE MUSCLE.
AS WELL.
AND AGAIN, THAT REBOUND AFTER AN
ORAL GLUCOSE TOLERANCE TEST OR
AN INTRAVENOUS GLUCOSE TOLERANCE
TEST, WHEN ADIPOSE HAS BEEN
TURNED OFF FOR THREE, FOUR HOURS
AND THEN IT START TO RELEASE
FATTY ACIDS, YOU END UP WITH A
FREE FATTY ACID CONCENTRATION
HIGHER THAN FASTING.
SO THERE IS A CONTROL THERE THAT
IS NOT STRAIGHTFORWARD, TURN
ADIPOSE OFF, TURN IT ON AGAIN.
THERE'S SOMETHING ELSE GOING ON.
>> DR. PARKS, I JUST WANT TO
CONGRATULATE YOU FIRST OF ALL ON
THIS WONDERFUL BODY OF WORK AND
SORT OF TAKING US THROUGH THIS
JOURNEY OF LEARNING OVER THE
LAST COUPLE OF DECADES.
I KNOW IT'S BEEN A LOT AND WE
ALL APPRECIATE IT.
I THINK MY QUESTION GOES TO THE
REGULATORS OF DNL, AND YOU SHOW
PRETTY CONVINCINGLY THAT SUGARS
ARE AN IMPORTANT PART OF THAT.
I KEEP GOING BACK TO THE SECOND
OR THIRD SLIDE YOU SHOWED WITH
THE ATHLETE YOU MENTIONED.
IS THERE ANYTHING ELSE?
COULD THERE ALSO BE A GENOTYPE
DIFFERENCE OR EPIGENETIC
INFLUENCES THAT WOULD ALTER DNL
RATE OR PROPENSITY FOR --
>> THANK YOU FOR ASKING THE
QUESTION ABOUT GENOTYPE.
AND I'VE SAID THIS THE LAST
YEAR, I THINK, TWICE IN TALKS.
NO ONE HAS MEASURED LIPOGENESIS
IN FAMILIES.
WE DON'T KNOW HOW HERITABLE IT
IS.
IT'S A HUGE GAP.
AND ALSO TO SEE THE SUBJECTS,
THE FEW SUBJECTS WITH FATTY
LIVER WHO LOST WEIGHT,
EQUIVALENT AMOUNTS OF WEIGHT BUT
THEIR LIVER FAT DIDN'T COME WAY,
WAY DOWN, THEY JUST SAT THERE AT
7%, WHAT'S GOING ON WITH THEM?
BECAUSE THEY HAD IMPROVEMENTS IN
INSULIN SENSITIVITY.
AND SO I THINK FOR ME, THAT'S
THE FUTURE BECAUSE IT WILL HELP
US UNDERSTAND HOW TO TREAT FATTY
LIVER DISEASE SPECIFICALLY
TARGETING THE FLUX -- PATHWAY.
THERE ARE ARGUMENTS IN MY FIELD
OF WHETHER IT'S INSULIN THAT
TURNS ON LIPID SYNTHESIS OR
HORMONE CHRBP OR IS IT JUST
CARBONS FLOWING DOWN GLYCOLYSIS.
AND FRUCTOSE, YOU MIGHT
REMEMBER, ENTERS GLYCOLYSIS
AFTER THE CONTROL STEP, WHICH IS
AT THE TOP.
YOU'VE GOT A POLICEMAN AT THE
TOP AND SOMEONE COMING IN ON THE
STREET IN THE MIDDLE.
SO IT DOESN'T MATTER HOW MUCH
CONTROL YOU GIVE, FRUCTOSE
FLOODS THE GLYCOLYTIC PATHWAY
AND IT IS THE MOST LIPOGENIC AND
AS YOU KNOW, IT DOESN'T RAISE
INSULIN VERY MUCH, SO THERE ARE
A LOT OF DATA TO SUGGEST IT'S
SIMPLY TOO MANY CARBONS, TOO
MUCH GOING DOWN THROUGH
GLYCOLYSIS.
>> THANK YOU.
>> THANKS.
>> HI, DR. PARKS.
I'VE BEEN A FAN OF YOURS
FOREVER.
BRILLIANT WORK.
I DID MY PH.D. IN FATTY LIVER,
SO I SO APPRECIATE YOUR
CONTRIBUTIONS.
THIS HAS BEEN A BURNING
QUESTION, AND I WAS ASKED IN MY
COMPREHENSIVE EXAMS, AND I SAID
ONE DAY I'M GOING TO SEE HER AND
I'M GOING TO ASK HER THIS.
YOU PROBABLY KNOW IT.
BUT I THINK MY QUESTION HAS
ALWAYS BEEN, YOU KNOW, WE THINK
THAT FATTY LIVER AND ALL OF THE
WAYS THAT IT IS IS THIS
INCREASED DEPOSITION OF FAT IN
THE LIVER, AND WE THINK OF
PATIENTS WITH FATTY LIVER AS A
FAILURE OF TH GETTING THAT FAT .
AND SOMETHING THAT'S ALWAYS
PERPLEXED ME AND I THINK IT BEEN
IN THE LITERATURE AS WELL IS
THAT WE SEE INCREASES IN DNL
THAT YOU'VE NOTED ACROSS THE
BOARD, BUT WHAT HAPPENS TO VLDL
EXPORT IN THE LIVER?
SO IN OTHER WORDS, WE SEE THESE
INCREASES IN DNL, BUT WHAT HAS
REMAINED UNCLEAR TO ME IS, DOES
VLDL PRODUCTION INCREASE TO
MATCH THAT INCREASED LOAD?
AND IF IT DOESN'T, ARE THOSE THE
PATIENTS THAT PROGRESS ON TO
ADVANCED STAGES OF NASH?
>> THIS IS AN IMPORTANT QUESTION
THAT'S BEEN RAISED BY A NUMBER
OF EXPERTS.
I'VE EVEN HEARD PEOPLE SAY THAT
PESKY VLDL, THE LIVER IS NOT
PUTTING OUT ENOUGH TO RELIEVE
THE LIPID THAT'S STUCK.
THAT'S THE ONE WAY TO GET LIPID
OUT OF THE LIVER.
THIS WOULD BE -- TO GET THAT
MUCH EXPORT OF TRIGLYCERIDE OUT
OF THE LIVER, IT WOULD BE LIKE
TAKING YOUR VOLKSWAGEN ON THE
HIGHWAY AND GOING 400 MILES AN
HOUR.
IT'S NOT GOING TO HAPPEN.
SO IT IS NOT A FAILURE OF VLDL
EXPORT.
YOU CAN'T MAKE THAT MUCH TO BE
ABLE TO --
>> JUST OVERWHELMING.
>> YOU NEED TO MAKE KETONES,
BURN FATTY ACIDS.
THERE'S LOTS OF WAYS TO GET RID
OF FAT IN THE LIVER AND WE DON'T
ALWAYS BLAME ONE PATHWAY.
LIPID SYNTHESIS IS ELEVATED,
EXPORT IS ELEVATED, APOE B
SECRETION RATE IS ELEVATED.
SO IN MY VIEW, THE LIVER IS
DOING AS BEST IT CAN TO GET RID
OF THE EXCESS LIPID.
AND SO I DON'T THINK WE CAN TURN
THAT UP.
THAT'S NOT GOING TO BE
PHYSIOLOGICALLY POSSIBLE.
>> OKAY.
>> WE DO KNOW THAT PARTICLES ARE
BIGGER, AND THERE ARE MORE OF
THEM.
BUT YOU REALLY DON'T SEE FATTY
LIVER -- PATIENTS WITH FATTY
LIVER HAVING LOW VLDL SECRETION,
UNLESS IT'S AN APOE B GENETIC
DEFECT.
>> THANK YOU.
>> PLEASE JOIN ME IN THANKING
DR. PARKS FOR A FANTASTIC
PRESENTATION AND AN AMAZING BODY
OF WORK.
>> THANKS.
[APPLAUSE]