Fatty Liver Disease, Nonalcoholic, Susceptibility To, 1

Description

The accumulation of excess triglyceride in the liver, a condition known as hepatic steatosis (or fatty liver), is associated with adverse metabolic consequences including insulin resistance and dyslipidemia. Factors promoting deposition of fat in the liver include obesity, diabetes, insulin resistance, and alcohol ingestion. Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries. In a subset of individuals hepatic steatosis promotes an inflammatory response in the liver, referred to as steatohepatitis, which can progress to cirrhosis and liver cancer (summary by Romeo et al., 2008).

Cohen et al. (2011) reviewed nonalcoholic fatty liver disease.

Genetic Heterogeneity of Nonalcoholic Fatty Liver Disease

Another form of nonalcoholic fatty liver disease (NAFLD2; 613387) has been associated with variation in the APOC3 gene (107720).

Mapping

Nonalcoholic Fatty Liver Disease

In a genomewide association study of 1,032 African American, 696 European American, and 383 Hispanic individuals who obtained proton magnetic resonance spectroscopy of the liver to evaluate hepatic fat content, Romeo et al. (2008) found a significant association between hepatic fat content and rs738409 in the PNPLA3 gene (609567) on chromosome 22q13 (p = 5.9 x 10 (-10)). The variant is a C-to-G transversion resulting in an ile148-to-met (I148M) substitution. There was also a significant association between this SNP and hepatic inflammation (p = 3.7 x 10 (-4)). The association between rs738409 and hepatic fat content remained highly significant (p = 7.0 x 10(-14)) after adjustment for body mass index (BMI), diabetes status, ethanol use, as well as global and local ancestry, indicating that the allele is not associated with major alterations in glucose homeostasis or lipoprotein metabolism. Further screening identified a second variant in the PNPLA3 gene (rs6006460), resulting in a ser453-to-ile (S453I) substitution, that was associated with a significantly lower liver fat content particularly in African Americans. The effect of this variant was independent from that of rs738409.

Alcoholic Liver Disease

Tian et al. (2010) investigated the contributions of variants in the PNPLA3 gene to liver disease in Mestizo subjects with a history of alcohol dependence (103780). Tian et al. (2010) genotyped 305 individuals with a history of alcohol dependence but apparently normal liver function (controls), 434 with intermediate alcoholic liver disease (ALD), and 482 with clinically evident alcoholic cirrhosis. Diagnoses were based on biochemical and clinical assessments supported by imaging, with histologic confirmation. Tian et al. (2010) found that rs738409 in PNPLA3 is strongly associated with alcoholic liver disease and clinically evident alcoholic cirrhosis (unadjusted odds ratio = 2.25, P = 1.7 x 10(-10); ancestry-adjusted odds ratio = 1.79, P = 1.9 x 10(-5)). Further tests showed no association of rs738409 with other covariates such as age, alcohol intake, and duration of intake. Tian et al. (2010) concluded that the rs738409 variant accounts for a substantial share of the increased risk of cirrhosis associated with Hispanic ancestry. They stated that the effect size of rs738409 is large for an association with complex disease in humans and may be the largest known genetic modifier for a disease that is a major cause of preventable death.

Population Genetics

The propensity to develop hepatic steatosis differs among ethnic groups, with African-Americans having a lower (24%) and Hispanics a higher (45%) frequency of the disorder than European-Americans (33%) in a study of a large American urban population (Browning et al., 2004). Hispanics also have a higher prevalence of steatohepatitis and cirrhosis, whereas African-Americans are less prone to develop liver failure (Browning et al., 2004).

Pathogenesis

Henao-Mejia et al. (2012) demonstrated that NLRP6 (609650) and NLRP3 (606416) inflammasomes and the effector protein IL18 (600953) negatively regulate nonalcoholic fatty liver disease/nonalcoholic steatohepatitis progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models revealed that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 (603030) and TLR9 (605474) agonists into the portal circulation, leading to enhanced hepatic tumor necrosis factor (TNF)-alpha (191160) expression, which drives NASH progression. Furthermore, cohousing of inflammasome-deficient mice with wildtype mice resulted in exacerbation of hepatic steatosis and obesity. Thus, Henao-Mejia et al. (2012) concluded that altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of theretofore seemingly unrelated systemic autoinflammatory and metabolic disorders.

Ma et al. (2016) demonstrated, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to accelerated hepatocarcinogenesis. They also showed that CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted hepatocellular carcinoma. Ma et al. (2016) concluded that their results provided an unexpected link between lipid dysregulation and impaired antitumor surveillance.