A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans

Abstract

Aims/hypothesis It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. Methods We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic-hyperinsulinaemic (insulin infusion 0.3 mU kg −1 min Results The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p=0.011) and serum aspartate aminotransferase concentrations (p=0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r=0.62, p<0.0001) and to liver fat content (r=0.58, p=0.025) in participants who were not morbidly obese (BMI <40 kg/m 2 ). Conclusions/interpretation A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.

PNPLA3 gene in liver diseases

“…The association between PNPLA3 variants and elevated ALT in the general population [7][8][9], or in patients with steatosis assessed by proton magnetic resonance spectroscopy [10], was also reported by various other teams. Interestingly, Sookoian et al replicated the findings of Romeo et al [6] in NAFLD and extended the association to histological severity, including nonalcoholic steatohepatitis (NASH), after adjustment for age, sex, BMI, and insulin resistance [11].…”

Variant in PNPLA3 is associated with alcoholic liver disease

“…This study gave additional support to the hypothesis that rs738409 [G] may confer increased susceptibility to hepatic injury. These associa tions have recently been confirmed in additional cohorts 6,7 .…”

“…The gene is highly expressed in adipocytes and liver 7 , and the protein may have a role in energy homeostasis 13 . Obesity and diabetes are known risk factors for non alcoholic as well as alcoholic liver disease, and expression of PNPLA3 is correlated with obesity 6 . However, studies associating rs738409 with liver dysfunction have not detected associations with systemic metabolic phenotypes, including obesity, plasma lipid levels or insulin resistance 4,6 .…”

“…Obesity and diabetes are known risk factors for non alcoholic as well as alcoholic liver disease, and expression of PNPLA3 is correlated with obesity 6 . However, studies associating rs738409 with liver dysfunction have not detected associations with systemic metabolic phenotypes, including obesity, plasma lipid levels or insulin resistance 4,6 . These and other results 7 suggest that rs738409 is an independent risk factor for liver dysfunction.…”

Les protéines à domaine patatine

“…Des expériences de surexpression et de perturbation de l'expression du gène par ARN interférence n'indiquent qu'un très modeste effet sur la lipolyse ou le contenu en triglycérides [29,33]. Très récemment, une étude d'association génétique a mis en évidence un lien entre la quantité de triglycérides hépatiques et des variants génétiques de l'adiponutrine, faisant de ce gène un facteur génétique majeur associé à la stéatosique hépatique non alcoolique et à ses complications inflammatoires [34][35][36][37]. Il est intéressant de remarquer qu'une surexpression de l'adiponutrine est observée dans le foie stéatosique de souris ob/ob [29] et que son expression hépatique chez l'homme est positivement corrélée au contenu en triglycérides hépatiques [37].…”