Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent

Abstract

Context: The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m À2 also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia. Objective: To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae. Participants and methods: The study was carried out in 678 obese Italians (mean BMI ¼ 41 kg m À2 ) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests. Main outcome measures: Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured. Results: Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P ¼ 2.2 Â 10 À5 and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (440 U l À1 ) compared with 25% of 148I allele homozygotes (P ¼ 0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes. Conclusion: Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.

Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

“…The PNPLA3 148MM/148MI group did not display hypertriglyceridemia or a low HDL cholesterol concentration. This is in line with most previous studies showing that carriers of the I148M variant lack the lipid changes usually accompanying increased liver fat content (5,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Serum total triglycerides tended to be even slightly lower in the PNPLA3 148MM/148MI than in the PNPLA3 148II group (Table 1), which is in keeping with recent studies including those performed in Danes (32), Japanese (33), and morbidly obese Swedes (34).…”

Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents

“…In the present cohort including only adolescents referred for suspected metabolic disease, we did not detect any interaction between PNPLA3 I148M and body fat in the pathogenesis of NAFLD. However, it could be speculated that the association between the 148M risk allele with higher BMI (as PNPLA3 I148M does not affect body fat at population level) is due to the interaction between this genetic factor and weight in determining higher ALT levels leading to patients referral (Romeo et al 2010). Although a higher intake of fast food, soft drinks, and meat has previously been associated with NAFLD in adults (Nobili et al 2013), an association between dietary patterns, occurrence of obesity, and development of NAFLD has not been reported in pediatric age.…”

Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

“…Substantial data support an important role for PNPLA3 in normal metabolism and disease including the following: i ) PNPLA3 shares signifi cant homology with proteins known to play critical roles in metabolism ( 9,64,65 ); ii ) PNPLA3 is highly regulated by important nutritional/metabolic factors ( 25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42); iii ) PNPLA3 expression is altered in obese/dysmetabolic states ( 25,(27)(28)(29); iv ) PNPLA3 has lipid hydrolase and transacylase activities in vitro ( 28,43,44 ); and v ) Genetic variation in PNPLA3 is associated with NAFLD in humans (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Despite this strong evidence, the in vivo function and physiological relevance of PNPLA3 remain unclear.…”

“…Recently, genetic variation in the human PNPLA3 gene (i.e., the rs738409 I148M allele in particular) has been strongly and repeatedly associated with hepatic TAG content, hepatocellular injury, and progression of NAFLD in humans (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). PNPLA3 variants have also been associated with obesity and features of the metabolic syndrome in humans in several studies ( 16,25,26 ), although subsequent studies have not confi rmed this association ( 10,12,18,22 ).…”