, 1519 (2011);
, et al. Jonathan C. Cohen
Human Fatty Liver Disease: Old Questions and New Insights
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About one-third of individuals with NAFLD
Of these individuals, 20 to 30% progress to se-
vere fibrosis within 10 years (41). The factors
causing progression of NAFLD to fibrosis and
because of the relative inaccessibility of liver tis-
sue.Unfortunately,no animal model recapitulates
(4). Nevertheless, studies in animal models have
ulate the cardinal features of NASH: hepatocyte
damage, inflammation, and fibrosis. Inflamma-
and fibrosis in liver.A growing body of evidence
and interleukin 6 (IL-6) (42) in the development
in rodents (43). A second potential mechanism is
ER stress, which results from improperly folded
unfolded protein response (UPR). The UPR acti-
vates nuclear factor kB, c-Jun N-terminal kinase,
and oxidative stress pathways, all of which have
been implicated in progression of steatosis to
Extrahepatic factors may also contribute to
NAFLD development and progression. Up to
70% of individuals undergoing liver transplanta-
tion for NASH or cryptogenic cirrhosis develop
NAFLD in the transplanted liver, although the
number of studies is small and factors such as
immunosuppressive drugs may play a role (45).
Evidence from mice suggest that increased ex-
posure of hepatocyctes to saturated fatty acids
like receptors and apoptosis by activating death
chondrial function and induce the ER stress path-
way in model organisms [see (46) for review].
Longitudinal studies of NAFLD show that a
substantial number of individuals (up to 20 to
30%) improve between biopsies, suggesting that
the disease might improve without treatment in
some individuals (41). Striking reductions in he-
patic TG content have been seen after bariatric
surgery. A recent meta-analysis of 15 studies that
included 766 paired liver biopsies revealed that
bariatric surgery improved steatosis in 92% of pa-
tients, improved steatohepatitis in 81%, and led
to complete resolution in 70% (47). Diet-induced
weight loss with increased physical activity has
also been shown to be associated with improve-
an antioxidant (vitamin E) and an insulin sensi-
NAFLD is a major health problem that has ac-
companied the trend toward an unhealthy diet.
With recent advances in the prevention and treat-
ment of hepatitis C, NAFLD is poised to become
the primary indication for liver transplantation.
Of greatest concern is the increased prevalence
of hepatic steatosis in children, where the disease
morbidity associated with NAFLD, many ques-
tions remain regarding the pathogenesis, natural
history, and treatment of this disorder. For exam-
ple, why is the frequency of NAFLD lower in
individuals of African descent even though the
prevalence of obesity and insulin resistance is
high in this group? Elucidating the molecular
therapeutic targets for the treatment of NAFLD
A critical question is whether hepatic TG ac-
cumulation alone is sufficient to cause disease
progression in NAFLD. Is the increase in NASH
conferred solely by increasing liver TG content,
or does the variant have other adverse effects? In
the Dallas Heart Study, the effect of PNPLA3 on
liver enzyme levels is abolished after controlling
for liver TG content. Some patients with primary
homozygous familial hypobetalipoproteinemia
or with neutral lipid storage disease, develop cir-
rhosis (12). However, these disorders are uncom-
mon, and only a minority of patients progress to
cirrhosis. Thus, it is not clear whether the liver
disease in these individuals is due solely to the
accumulation of TG in hepatoctyes.
Improved methods for early detection of
NASH are urgently needed. Hepatic steatosis
can be diagnosed noninvasively, but determining
requires a liver biopsy, which is usually reserved
for individuals with elevated levels of circulating
increases the likelihood of having NASH, up to
59% of individuals with hepatic steatosis and
normal ALTs have NASH on biopsy (51). Some
patients with NAFLD present for the first time
ods that detect inflammation and fibrosis in the
liver are needed to more fully capture the natural
history of this disorder and to test therapeutic
approaches designed to halt or reverse disease
progression. A further impediment toward the
development of new therapeutic interventions is
the lack of an animal model that fully recapitu-
lates all the features of NAFLD (4). Until such a
model becomes available, human genetic studies
provide a good opportunity for delineating the
molecular pathways that lead to steatosis, steato-
hepatitis, and cirrhosis.
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Acknowledgments: We thank T. Rodgers for the histological
sections in Fig. 1 and D. Russell, J. Goldstein, M. Brown,
and J. Browning for helpful discussions. The University
of Texas Southwestern Medical Center has applied to
patent the association between rs738409 and NAFLD.
Supported by grants from the NIH (RL1HL092550,
UL1DE109584, and PO1 HL20948). H.H.H. is on the
Scientific Advisory Board for Pfizer. J.D.H. is a consultant
for Merck, Pfizer, and Sanofi-Aventis and is on the
Scientific Advisory Board of Aegerion.
VOL 332 24 JUNE 2011
on July 31, 2011