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Human Fatty Liver Disease: Old Questions and New Insights
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Human Fatty Liver Disease:
Old Questions and New Insights
Jonathan C. Cohen,1Jay D. Horton,1,2Helen H. Hobbs1,2,3*
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third
of adults and an increasing number of children in developed countries. The disease begins with
the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an
inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is
strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood,
and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD,
focusing primarily on those that have emerged from human genetic and metabolic studies.
energy demand and availability. The ubiquitous
selection of TG for this role is attributable to two
physicochemical properties: TGs provide greater
caloric density (9 kcal/g) than do carbohydrates
(4.5 kcal/g) or proteins (4 kcal/g), and TGs are
insoluble in water, so they can accumulate to
high levels with no adverse osmotic or colloidal
piled in adipocytes, and it accumulates in other
cell types only under unusual circumstances. For
example, migratory birds store large quantities of
TGs in the liver as an energy source in prepara-
tion for prolonged seasonal flights, a propensity
that has been exploited to produce the culinary
delicacy fois gras. Like migratory birds, some hu-
mans who consume excess calories deposit fat in
the liver. In humans, however, fatty liver is mal-
Nonalcoholic fatty liver disease (NAFLD) is
an umbrella term used to describe a range of
related disorders (Fig. 1). The earliest stage is
hepatic steatosis, which is characterized by the
deposition of TG as lipid droplets in the cyto-
plasm of hepatocytes. Steatosis is defined as a
hepatic TG level exceeding the 95th percentile
liver) or as the presence of cytoplasmic TG drop-
Hepatic steatosis is often self-limited, but it can
progressto NASH(nonalcoholic steatohepatitis).
NASH is distinguished from simple steatosis by
looning and cell death), an inflammatory infil-
trate, and/or collagen deposition (fibrosis) (Fig.
1B). It is not known whether steatosis always
arly in eukaryote evolution, triglycerides
(TGs) emerged as the preferred storage
nutrient to buffer against fluctuations in
precedes NASH or whether steatosis and NASH
are distinct disorders (Fig. 1A). NASH, in turn,
can progress to cirrhosis: Between 10 to 29% of
individuals with NASH develop cirrhosis within
by scar tissue composed primarily of type 1 col-
lagen. The collagen is produced by specialized
cells called stellate cells, which are activated by
Cirrhosis can ultimately progress to liver cancer
(Fig. 1A); 4 to 27% of individuals with NASH-
induced cirrhosis develop hepatocellular carcino-
ma (3). Hepatic TG content can be quantified by
noninvasive imaging modalities, but liver biop-
liver and the transition from steatosis to steato-
hepatitis and cirrhosis in humans have not been
clearly defined. Mouse models that recapitulate
certain features of the human disease continuum
have provided insights into possible pathological
mechanisms contributing to its development (4),
have not been conclusively determined. In this re-
emerged from human genetic studies. The recent
identification of sequence variations that are as-
of this increasingly common disorder (5, 6).
The Pathogenesis of Hepatic Steatosis
Hepatic steatosis arises from an imbalance be-
tween TG acquisition and removal. TGs are
the fatty acids used for hepatic TG formation are
derived from three sources: (i) diet, (ii) de novo
synthesis, and (iii) adipose tissue. Dietary fats
taken up in the intestine are packaged into TG-
rich chylomicrons and delivered to the systemic
circulation. In rats, ~80% of the TG in chylomi-
crons is hydrolyzed by lipoprotein lipase (LPL),
releasing free fatty acids (FFAs) for uptake by
peripheral tissues. The remaining ~20% is deli-
vered to the liver (7). Extrapolating from these
per day) furnishes the liver with ~20 g offateach
of an average liver.
Carbohydrate feeding promotes de novo syn-
thesis of FFA from acetyl–coenzyme A (CoA)
(Fig. 2) by increasing the level of insulin and
the availability of substrate. Insulin stimulates
binding protein–1c (SREBP-1c) via a signaling
cascade involving AKT2, LXR, and mTOR (8).
responsive element-binding protein (ChREBP)
(10). Like SREBP-1c, ChREBP stimulates the ex-
pression of multiple genes in the fatty acid bio-
expression of liver-type pyruvate kinase, thus
providing more substrate for FFA and TG syn-
During fasting, plasma levels of insulin fall,
whereas levels of glucagon and epinephrine in-
crease, stimulating TG hydrolysis in adipocytes
(Fig. 2). The first step in TG hydrolysis is cat-
alyzed by adipocyte TG hydrolase (ATGL) (11).
fates: They can be oxidized in mitochondria to
produce energy and ketone bodies, reesterified
to TG and stored in lipid droplets, or coupled to
apolipoproteins and secreted as a constituent of
very-low-density lipoproteins (VLDL). FFAs in
liver are also incorporated into phospholipids
and other lipids. The flux of FFA through the cir-
culation amounts to ~100 g/day with 20% being
extracted by the liver. Thus, the daily input of
TG from the diet (~20 g/day) and FFA from ad-
TG content of the liver.
Studies of humans with rare inherited dis-
adipose tissue to the liver, or increased de novo
lipogenesis results in hepatic steatosis (12). Con-
genital generalized lipodystrophy is invariably
associated with severe hepatic steatosis (12). Gly-
cogen storage disease type 1a and citrin deficien-
cause massive hepatic steatosis even in the ab-
sence of obesity or insulin resistance (13, 14).
chondrial aspartate-glutamate transporter. Inacti-
exchange, resulting in an increase in cytoplasmic
citrate, which is converted to acetyl-CoA.
Genetic defects that prevent the removal of
TG from the liver also cause steatosis. Muta-
tions in ATGL or its cofactor, comparative gene
identification–58 (CGI-58), prevent mobilization
of FFA from lipid droplets (Fig. 2). Defects in
the enzymes required for oxidation of FFA in
1Department of Internal Medicine, University of Texas South-
ment of Molecular Genetics, University of Texas Southwestern
Medical Institute, University of Texas Southwestern Medical
Center, Dallas, TX 75390–9046, USA.
*To whom correspondence should be addressed. E-mail:
VOL 33224 JUNE 2011
on July 31, 2011
pathway for hepatic TGs is secretion into the
blood as VLDL (Fig. 2). Mutations in the struc-
tural protein of VLDL [apolipoprotein (apo)B] or
in the protein that adds TG to the nascent lipo-
(microsomal TG transfer protein, MTTP) are ad-
erozygous for inactivating mutations in APOB
produce fewer VLDL particles and have a three-
fold increase in hepatic TG relative to healthy
Whereas single-gene mutations cause rare
forms of severe steatosis, the increased preva-
lence of NAFLD in the general population over
and composition of food (Fig. 2). The cardinal
role of obesity in the development of hepatic ste-
For example, in the Dallas Heart Study, a multi-
ethnic population-based sample that included
more than 2000 individuals from Dallas, Texas,
hepatic steatosis is uncommon among lean indi-
viduals [9% in individuals with body mass in-
dex (BMI) < 25 kg/m2] and highly prevalent
among the severely obese (51% in individuals
with BMI > 35 kg/m2) (16). Food composition
also influences hepatic fat deposition. Carbohy-
drates in general and fructose in particular play
important roles. Fructose consumption routes
dietary carbons directly to the liver in a form that
is primed to enter biosynthetic pathways, includ-
ing de novo lipogenesis. Unlike glucose, circu-
(17). Because fructose is phosphorylated at car-
bon 1 rather than carbon 6, it cannot be used to
Fig. 1. Thediseasespectrumofnonalcoholicfattyliverdisease.(A)Schematic
of progression of NAFLD. The accumulation of TG within lipid droplets in hepa-
fibrosis is referred to as NASH, which can progress to cirrhosis. Individuals with
cirrhosis have an increased risk of hepatocellular carcinoma. (B) Histological sec-
tions illustrating normal liver, steatosis, NASH, and cirrhosis. Collagen fibers are
24 JUNE 2011VOL 332
on July 31, 2011
synthesize glycogen but instead is quantitative-
viding substrate for de novo lipogenesis. The
average yearly consumption of fructose has pro-
gressively increased and likely contributes to the
increasing prevalence of NAFLD.
What Is the Relationship Between Obesity,
Insulin Resistance, and Hepatic Steatosis?
The finding that genetic diseases that promote
flux of energy substrates to fatty acids, such as
glycogen storage disease type 1a and citrin defi-
ciency, cause steatosis even in the absence of in-
In obese individuals, the increased supply of
FFA to the liver from the diet, from adipose tis-
sue, and through increased de novo lipogenesis
contributions of the three pathways to hepatic
study: Donnelly et al. (18) reported that 59% of
hepatic fat is derived from circulating FFAs, with
lesser contributions from de novo lipogenesis
(26%) and diet (15%).
motes fatty acid synthesis. With the development
of hepatic insulin resistance, the inhibitory effect
of insulin on glucose production is diminished,
esis is retained (19). Insulin resistance is strongly
correlated with steatosis, and interventions that
levels and decreased liver fat content. Multiple
animal models support a direct causal relation-
ship between insulin resistance, hyperinsulinemia,
and hepatic steatosis (4). Evidence that insulin
patients with mutations in AKT2 (20). These pa-
tients have profound resistance to the glucoreg-
ulatory actions of insulin but presumably retain
Studies of metastatic insulin-secreting tumors
plants provide further evidence that insulin di-
rectly promotes fat accumulation in liver cells.
Hepatocytes surrounding metastatic insulinomas
become engorged with TGs, as do hepatocytes
surrounding transplanted islet cells (21).
and insulin resistance has led to the hypothesis
that excess TG in liver causes insulin resistance.
Hepatic steatosis and insulin resistance occur to-
gether in several strains of genetically modified
mice (4, 22). However, the notion that hepatic
steatosis causes insulin resistance is contradicted
by observations in mice with defects in diverse
pathways that cause hepatic steatosis without in-
sulin resistance. Mice with reduced fatty acid syn-
thesis (23), mobilization (24), or oxidation (4), as
well as defective cytokine signaling (25) or cho-
line synthesis (26), maintain normal or improved
accumulation. TG may be a marker
for another molecule that interferes
with insulin action, such as diacyl-
or ceramide. However, hepatic accu-
mulation of any of these lipids does
not invariably produce insulin resist-
ance, at least in mice [for review, see
(22)]. It remains possible that these
lipids contribute to insulin resistance
only if they accumulate within spe-
cific subcellular compartments or if
tations provide a powerful tool to
untangle mechanistic relationships
between highly correlated metabolic
causes insulin resistance, then indi-
mote hepatic steatosis should be at
increased risk of developing insulin
resistance. An increasing number of
Mendelian genetic defects have un-
coupled these two variables. Individ-
uals with inactivating mutations in
APOB have increased levels of he-
patic TG yet maintain normal insulin
sensitivity (15). Patients with auto-
somal recessive disorders caused by
mutations in either ATGL or CGI58
have severe steatosis but are not insulin resistant
[reviewed in (12)]. In population-based studies, a
hepatic steatosis is not associated with insulin re-
sistance (see below) (5). Sequence variants in
APOC3 have been associated with both hepatic
steatosis and insulin resistance (25), but this as-
sociation was not observed in other independent
populations (26, 27). Thus, the preponderance of
evidence is not compatible with the hypothesis
that TG accumulation in hepatocytes causes in-
sulin resistance in humans.
Genetic Risk Factors for Hepatic Steatosis
Although obesity and insulin resistance are the
most prevalent risk factors for NAFLD, hepatic
with equivalent adiposity, indicating that other
factors contribute to this condition. One of these
factors is gender. Before age 60, men are signif-
icantly more likely to develop steatosis than are
women (16), but at older ages the disorder is
more prevalent in women. Reasons for this gen-
der dimorphism are not known. Another factor
is ethnicity. In the Dallas Heart Study, hepatic
steatosis was found in 45% of Hispanics, 33% of
individuals of European ancestry, and 24% of
African Americans (16). The higher prevalence
of hepatic steatosis in Hispanics is due in part to
a higher prevalence of obesity and insulin resist-
ance in this population, but the lower prevalence
in African Americans cannot be explained by
Fig. 2. Metabolism of TG in the liver. The three major sources of FFAs are diet, endogenous synthesis, and peripheral
tissues. FFAs have four possible fates. They can be metabolized by b oxidation (b-OX) in mitochondria, esterified and
blood. Processes that increase FFA and TG input or reduce FFA and TG output cause hepatic steatosis. Carbohydrate
intake increases glucose and insulin levels, which activate two transcription factors in the liver that promote de novo
lipogenesis: ChREBP and SREBP-1c. Insulin inhibits lipolysis in adipose tissue by suppressing ATGL. Chylo, chylo-
micron; TCA, tricarboxylic acid.
VOL 33224 JUNE 2011
on July 31, 2011
ethnic differences in BMI, insulin resistance, eth-
anolingestion,or medication use.Another ethnic
group with an increased prevalence of hepatic
steatosis is Asian Indians. A study of 482 lean
young individuals revealed a twofold higher he-
patic TG content in Asian Indians than men of
European descent (28).
in families (29), with the heritability of NAFLD
being estimated to be ~39% (30). One genetic
is a missense mutation [Ile148→Met148(I148M)]
in patatin-like phospholipase domain–containing
(5). This variant was initially identified through
an association study of 9299 nonsynonymous se-
quence variations, and the relationship with he-
patic TG content has been confirmed in many
independent studies [for review, see (31)]. The
148M) in ethnic groups mirrors the prevalence of
in frequency of hepatic steatosis between His-
panics, African Americans, and individuals of
European descent (5). Homozygotes for the risk
allele in PNPLA3 (MM) have a ~twofold higher
hepatic TG content, although the magnitude of
the effect is strongly influenced by adiposity and
PNPLA3 is a member of the PNPLA family,
(11). PNPLA3 is most highly expressed in adi-
pose tissue and liver and is transcriptionally reg-
ulated byinsulinthrough asignalingcascadethat
includes LXR and SREBP-1c; hepatic PNPLA3
mRNA levels are reduced to nearly undetectable
levels during fasting and increase 80-fold with
in hepatocytes is located in lipid droplets, which
are specialized organelles that participate in pro-
tein partitioning, trafficking, and degradation [for
review, see (33)].
The physiological role of PNPLA3 and the
mechanism by which the I148M isoform causes
fatty liver are not known. The purified protein
has both TG hydrolase and transacylase activity
(34, 35). The I148M substitution markedly re-
ing that the I148M substitution causes a loss of
fails to increase hepatic TG content (36, 37), and
I148M in mouse liver causes an increase in he-
patic TG content (35), which is more consistent
with the I148M substitution conferring a gain of
function. Additional studies will be required to de-
termine the molecular mechanism by which varia-
A recent genome-wide association study of
hepatic steatosis in 7176 participants (6) revealed
additional susceptibility loci for NAFLD. Sur-
prisingly, none of the newly identified genomic
intervals contained genes associated with rare
Mendelian disorders of hepatic steatosis, such as
APOB, ATGL, CGI-58, or genes associated with
lipodystrophy. The allele of greatest effect size
was PNPLA3-I148M, which conferred an odds
ratio for NAFLD of 3.26. The other genomic re-
gions associated with hepatic steatosis in this
study included NCAN and PPP1R3B (Table 1).
Analysis of an independent cohort with histolog-
between NAFLD and the other two implicated
genes, NCAN and LYPLAL1, remains to be de-
fined. Elucidation of the roles of these genes may
provide new insights into the metabolic pathways
that contribute to common forms of NAFLD in
What Factors Contribute to NAFLD Progression?
The PNPLA3 allele associated with steatosis is
also associated with elevated serum levels of
alanine transaminase (ALT) (5, 38), an enzyme
PNPLA3-I148M may also contribute more gen-
erally in the response of the liver to injury. In
support of this notion, PNPLA3-148M greatly
increases the odds of developing cirrhosis in al-
coholics (40). The finding that PNPLA3 is asso-
provides strong molecular evidence that NAFLD
Table 1. Common variants associated with nonalcholic fatty liver disease. Odds ratios for NAFLD were calculated by using cases with biopsy-proven
NAFLD and in ancestry-matched controls (6). EA, European American; AA, African American; ND, not determined.
Gene (first report) Protein Function
PNPLA3 (5) Patatin-like
subunit of protein
0.23 in EA
0.49 in Hispanics
0.17 in AA
rs42406240.08 YesNo 0.93
NCAN (6) Neurocan rs2228603
0.07 YesYes 1.65 ND
GCKR (6) Glucokinase
LYPLAL1 (6) Lysophospholipase-like 1rs12137855 0.21No Yes
APOC3 (25) Apolipoprotein C3 Limits
0.38 in EA
0.38 in Hispanics
0.71 in AA
0.26 in EA
0.32 in Hispanics
0.66 in AA
Yes* ND ND
*The association was found in Asian-Indian men and replicated in a group of mixed ethnicity (25). The association was not observed in (26, 27).
24 JUNE 2011VOL 332
on July 31, 2011
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.
References and Notes
1. L. S. Szczepaniak et al., Am. J. Physiol. Endocrinol.
Metab. 288, 462 (2005).
2. C. K. Argo, S. H. Caldwell, Clin. Liver Dis. 13, 511 (2009).
3. B. Q. Starley, C. J. Calcagno, S. A. Harrison, Hepatology
51, 1820 (2010).
4. L. Hebbard, J. George, Nat. Rev. Gastroenterol. Hepatol.
8, 35 (2011).
5. S. Romeo et al., Nat. Genet. 40, 1461 (2008).
6. E. K. Speliotes et al., PLoS Genet. 7, e1001324
7. T. G. Redgrave, J. Clin. Investig. 49, 465 (1970).
8. S. Li, M. S. Brown, J. L. Goldstein, Proc. Natl. Acad.
Sci. U.S.A. 107, 3441 (2010).
9. J. D. Horton, J. L. Goldstein, M. S. Brown, J. Clin. Investig.
109, 1125 (2002).
10. K. Uyeda, J. J. Repa, Cell Metab. 4, 107 (2006).
11. R. Zimmermann et al., Science 306, 1383 (2004).
12. A. J. Hooper, L. A. Adams, J. R. Burnett, J. Lipid Res. 52,
13. R. H. Bandsma et al., Pediatr. Res. 63, 702 (2008).
14. M. Komatsu et al., J. Hepatol. 49, 810 (2008).
15. T. Tanoli, P. Yue, D. Yablonskiy, G. Schonfeld, J. Lipid Res.
45, 941 (2004).
16. J. D. Browning et al., Hepatology 40, 1387 (2004).
17. L. Tappy, K. A. Lê, Physiol. Rev. 90, 23 (2010).
18. K. L. Donnelly et al., J. Clin. Investig. 115, 1343
19. M. S. Brown, J. L. Goldstein, Cell Metab. 7, 95 (2008).
20. R. K. Semple et al., J. Clin. Investig. 119, 315 (2009).
21. R. Bhargava et al., Diabetes 53, 1311 (2004).
22. C. A. Nagle, E. L. Klett, R. A. Coleman, J. Lipid Res. 50
(suppl.), S74 (2009).
23. M. V. Chakravarthy et al., Cell Metab. 1, 309 (2005).
24. J. M. Brown et al., J. Lipid Res. 51, 3306 (2010).
25. K. F. Petersen et al., N. Engl. J. Med. 362, 1082
26. J. Kozlitina, E. Boerwinkle, J. C. Cohen, H. H. Hobbs,
Hepatology 53, 467 (2011).
27. P. J. Michel et al., Hepatology, published online 4 April
28. K. F. Petersen et al., Proc. Natl. Acad. Sci. U.S.A. 103,
29. V. M. Struben, E. E. Hespenheide, S. H. Caldwell,
Am. J. Med. 108, 9 (2000).
30. J. B. Schwimmer et al., Gastroenterology 136, 1585
31. S. Romeo, I. Huang-Doran, M. G. Baroni, A. Kotronen,
Curr. Opin. Lipidol. 21, 247 (2010).
32. Y. Huang et al., Proc. Natl. Acad. Sci. U.S.A. 107,
33. M. A. Welte, Trends Cell Biol. 17, 363 (2007).
34. C. M. Jenkins et al., J. Biol. Chem. 279, 48968
35. S. He et al., J. Biol. Chem. 285, 6706 (2010).
36. W. Chen, B. Chang, L. Li, L. Chan, Hepatology 52,
37. M. K. Basantani et al., J. Lipid Res. 52, 318 (2011).
38. X. Yuan et al., Am. J. Hum. Genet. 83, 520 (2008).
39. S. Sookoian et al., J. Lipid Res. 50, 2111 (2009).
40. C. Tian, R. P. Stokowski, D. Kershenobich, D. G. Ballinger,
D. A. Hinds, Nat. Genet. 42, 21 (2010).
41. C. K. Argo, P. G. Northup, A. M. Al-Osaimi, S. H. Caldwell,
J. Hepatol. 51, 371 (2009).
42. A. E. Feldstein, Semin. Liver Dis. 30, 391 (2010).
43. H. Tilg, Dig. Dis. 28, 179 (2010).
44. G. S. Hotamisligil, Cell 140, 900 (2010).
45. S. M. Malik et al., Liver Transpl. 15, 1843 (2009).
46. N. Alkhouri, L. J. Dixon, A. E. Feldstein, Expert Rev.
Gastroenterol. Hepatol. 3, 445 (2009).
47. R. R. Mummadi, K. S. Kasturi, S. Chennareddygari,
G. K. Sood, Clin. Gastroenterol. Hepatol. 6, 1396
48. N. A. Johnson, J. George, Hepatology 52, 370 (2010).
49. A. J. Sanyal et al., N. Engl. J. Med. 362, 1675 (2010).
50. J. B. Schwimmer et al., Pediatrics 118, 1388 (2006).
51. A. L. Fracanzani et al., Hepatology 48, 792 (2008).
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.
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