Excessive fructose consumption may cause a leaky gut, leading to fatty
liver disease

Date:
August 24, 2020
Source:
University of California - San Diego
Summary:
Excessive consumption of fructose -- a sweetener ubiquitous in the
American diet -- can result in non-alcoholic fatty liver disease
(NAFLD), which is comparably abundant in the United States. But
contrary to previous understanding, researchers report that fructose
only adversely affects the liver after it reaches the intestines,
where the sugar disrupts the epithelial barrier protecting internal
organs from bacterial toxins in the gut.



FULL STORY ========================================================================== Excessive consumption of fructose -- a sweetener ubiquitous in the
American diet -- can result in non-alcoholic fatty liver disease (NAFLD),
which is comparably abundant in the United States. But contrary to
previous understanding, researchers at University of California San Diego School of Medicine report that fructose only adversely affects the liver
after it reaches the intestines, where the sugar disrupts the epithelial barrier protecting internal organs from bacterial toxins in the gut.


========================================================================== Developing treatments that prevent intestinal barrier disruption,
the authors conclude in a study published August 24, 2020 in Nature
Metabolism, could protect the liver from NAFLD, a condition that affects
one in three Americans.

"NAFLD is the most common cause of chronic liver disease in the
world. It can progress to more serious conditions, such as cirrhosis,
liver cancer, liver failure and death," said senior author Michael Karin,
PhD, Distinguished Professor of Pharmacology and Pathology at UC San
Diego School of Medicine.

"These findings point to an approach that could prevent liver damage from occurring in the first place." Fructose consumption in the U.S. has skyrocketed since the 1970s and the introduction of high fructose corn
syrup (HFCS), a cheaper sugar substitute that is broadly used in processed
and packaged foods, from cereals and baked goods to soft drinks. Multiple studies in animals and humans have linked increased HFCS consumption
with the nation's obesity epidemic and numerous inflammatory conditions,
such as diabetes, heart disease and cancer. The U.S.

Food and Drug Administration, however, currently regulates it similar to
other sweeteners, such as sucrose or honey, and advises only moderation
of intake.

The new study, however, defines a specific role and risk for HFCS in
the development of fatty liver disease. "The ability of fructose, which
is plentiful in dried figs and dates, to induce fatty liver was known
to the ancient Egyptians, who fed ducks and geese dried fruit to make
their version of foie gras," said Karin.

"With the advent of modern biochemistry and metabolic analysis, it
became obvious that fructose is two to three times more potent than
glucose in increasing liver fat, a condition that triggers NAFLD. And
the increased consumption of soft drinks containing HFCS corresponds
with the explosive growth in NAFLD incidence." Fructose is broken
down in the human digestive tract by an enzyme called fructokinase,
which is produced both by the liver and the gut. Using mouse models, researchers found that excessive fructose metabolism in intestinal
cells reduces production of proteins that maintain the gut barrier -- a
layer of tightly packed epithelial cells covered with mucus that prevent bacteria and microbial products, such as endotoxins, from leaking out
of the intestines and into the blood.



========================================================================== "Thus, by deteriorating the barrier and increasing its permeability,
excessive fructose consumption can result in a chronic inflammatory
condition called endotoxemia, which has been documented in both
experimental animals and pediatric NAFLD patients," said the study's
first author Jelena Todoric, MD, PhD, a visiting scholar in Karin's lab.

In their study, Karin, Todoric and colleagues from universities and institutions around the world, found that leaked endotoxins reaching
the liver provoked increased production of inflammatory cytokines
and stimulated the conversion of fructose and glucose into fatty acid
deposits.

"It is very clear that fructose does its dirty work in the intestine,"
said Karin, "and if intestinal barrier deterioration is prevented,
the fructose does little harm to the liver." The scientists noted that
feeding mice with high amounts of fructose and fat results in particularly severe adverse health effects. "That's a condition that mimics the 95th percentile of relative fructose intake by American adolescents, who
get up to 21.5 percent of their daily calories from fructose, often in combination with calorie-dense foods like hamburgers and French fries,"
Karin said.

Interestingly, the research team found that when fructose intake was
reduced below a certain threshold, no adverse effects were observed
in mice, suggesting only excessive and long-term fructose consumption represents a health risk.

Moderate fructose intake through normal consumption of fruits is well- tolerated.

"Unfortunately, many processed foods contain HFCS and most people cannot estimate how much fructose they actually consume," said Karin. "Although education and increased awareness are the best solutions to this problem,
for those individuals who had progressed to the severe form of NAFLD
known as nonalcoholic steatohepatitis, these findings offer some hope of
a future therapy based on gut barrier restoration." Co-authors include: Giuseppe Di Caro, Shabnam Shalapour, Reginald McNulty, Koji Taniguchi,
Courtney R. Green, Alison Vrbanac, Xiao Liu, Jeramie D. Watrous,
Rafael Moranchel, Mahan Najhawan, Christian M. Metallo, Rob Knight,
Mohit Jain,and Tatiana Kisseleva, all at UC San Diego; Saskia Reibe,
Garvan Institute of Medical Research; Darren C. Henstridge and Peter
J. Meikle, Baker Heart and Diabetes Institute; Mark A. Febbraio, Monash Institute of Pharmaceutical Sciences; Fatih Ceteci, Claire Conche and
Florian R. Greten, German Cancer Research Center; Maria T. Diaz-Meco
and Jorge Moscat, SBP Medical Discovery Institute; and Lester F. Lau, University of Illinois, Chicago School of Medicine.


========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Scott
LaFee. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jelena Todoric, Giuseppe Di Caro, Saskia Reibe, Darren
C. Henstridge,
Courtney R. Green, Alison Vrbanac, Fatih Ceteci, Claire Conche,
Reginald McNulty, Shabnam Shalapour, Koji Taniguchi, Peter
J. Meikle, Jeramie D.

Watrous, Rafael Moranchel, Mahan Najhawan, Mohit Jain, Xiao Liu,
Tatiana Kisseleva, Maria T. Diaz-Meco, Jorge Moscat, Rob Knight,
Florian R.

Greten, Lester F. Lau, Christian M. Metallo, Mark A. Febbraio,
Michael Karin. Fructose stimulated de novo lipogenesis is
promoted by inflammation. Nature Metabolism, 2020; DOI:
10.1038/s42255-020-0261-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200824131807.htm

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