Although obesity and insulin resistance are the most prevalent risk factors for NAFLD, hepatic fat content varies substantially among individuals with equivalent adiposity, indicating that other factors contribute to this condition. One of these factors is gender. Before age 60, men are significantly more likely to develop steatosis than are women (16
), but at older ages the disorder is more prevalent in women. Reasons for this gender 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 resistance in this population, but the lower prevalence in African Americans cannot be explained by ethnic differences in BMI, insulin resistance, ethanol ingestion, 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 hepatic TG content in Asian Indians than men of European descent (28
Hepatic steatosis, NASH, and cirrhosis cluster in families (29
), with the heritability of NAFLD being estimated to be ~39% (30
). One genetic variant that is consistently associated with NAFLD is a missense mutation [Ile148
(I148M)] in patatin-like phospholipase domain–containing (PNPLA) 3 gene PNPLA3
(also called adiponutrin) (5
). This variant was initially identified through an association study of 9299 nonsynonymous sequence variations, and the relationship with hepatic TG content has been confirmed in many independent studies [for review, see (31
)]. The frequency of the susceptibility variant (PNPLA3-148M) in ethnic groups mirrors the prevalence of NAFLD and accounts for ~70% of the differences in frequency of hepatic steatosis between Hispanics, 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 insulin sensitivity.
PNPLA3 is a member of the PNPLA family, most closely resembling ATGL (PNPLA2) () (11
). PNPLA3 is most highly expressed in adipose tissue and liver and is transcriptionally regulated by insulin through a signaling cascade that includes LXR and SREBP-1c; hepatic PNPLA3 mRNA levels are reduced to nearly undetectable levels during fasting and increase 80-fold with refeeding in mice (32
). Over 90% of the PNPLA3 in hepatocytes is located in lipid droplets, which are specialized organelles that participate in protein 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
). The I148M substitution markedly reduces TG hydrolase activity in vitro (35
), suggesting that the I148M substitution causes a loss of function. However, inactivation of Pnpla3
in mice fails to increase hepatic TG content (36
), and adenoviral-mediated overexpression of PNPLA3-I148M in mouse liver causes an increase in hepatic TG content (35
), which is more consistent with the I148M substitution conferring a gain of function. Additional studies will be required to determine the molecular mechanism by which variation in PNPLA3 confers susceptibility to NAFLD.
A recent genome-wide association study of hepatic steatosis in 7176 participants (6
) revealed additional susceptibility loci for NAFLD. Surprisingly, none of the newly identified genomic intervals contained genes associated with rare Mendelian disorders of hepatic steatosis, such as APOB
, 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 regions associated with hepatic steatosis in this study included NCAN
(). Analysis of an independent cohort with histologically defined NAFLD by the same group found an association with NCAN
, and LYPLAL1
but not with PPP1R3B
, with odds ratios ranging from 1.37 (LYPLAL1
) to1.65 (NCAN
). Loss-of-function alleles in GCKR
would be predicted to increase levels of glucose-6-phosphate and thus promote fatty acid synthesis. The mechanistic link between NAFLD and the other two implicated genes, NCAN
, remains to be defined. Elucidation of the roles of these genes may provide new insights into the metabolic pathways that contribute to common forms of NAFLD in the population.
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.