The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels

Abstract

The Ile148Met (rs738409, G-allele) in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) associates with liver fat content and may lead to loss-of-function (hydrolysis) or gain-of-function (CoA-dependent lysophosphatidic acid acyltransferase) defects. PNPLA3 is up-regulated by dietary carbohydrates, and interactions between rs738409 and carbohydrates, and sugar and ω6:ω3-polyunsaturated fatty acid (PUFA) ratio on hepatic fat accumulation have been reported. We examined interaction between rs738409 and overweight, and between rs738409 and dietary intakes (carbohydrates, sucrose and ω6:ω3-PUFA ratio), on fasting triglyceride levels. From the Malmo Diet and Cancer Study-Cardiovascular Cohort, 4,827 individuals without diabetes aged 58 ± 6 years, 2,346 with BMI ≤ 25 kg/m2 and 2,478 with BMI > 25 kg/m2, were included in cross-sectional analyses. Dietary data were collected by a modified diet history method. Overweight modified the association between rs738409 and fasting triglyceride levels (Pinteraction = 0.003). G-allele associated with lower triglycerides only among overweight individuals (P = 0.01). Nominally, significant interaction on triglyceride levels was observed between rs738409 and sucrose among normal-weight individuals (Pinteraction = 0.03). G-allele associated with lower triglycerides among overweight individuals in the lowest tertiles of carbohydrate and ω6:ω3-PUFA ratio (P = 0.04 and P = 0.001) and with higher triglycerides among normal-weight individuals in the highest tertile of sucrose (P = 0.001). We conclude that overweight and dietary sucrose may modify the association between rs738409 and fasting triglyceride levels.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-014-0388-4) contains supplementary material, which is available to authorized users.

Reduction of Caloric Intake Might Override the Prosteatotic Effects of the <b><i>PNPLA3</i></b> p.I148M and <b><i>TM6SF2</i></b> p.E167K Variants in Patients with Fatty Liver: Ultrasound-Based Prospective Study

“…Overall, differently tailored diets might be needed in over-and normal-weight individuals to diminish the harmful effects of the PNPLA3 allele. For example, Stojkovic et al [30] postulated that diet, especially sucrose, and overweight modulate the direction of the association between variant PNPLA3 and hepatic steatosis. Several reports showed that obese individuals who carry the PNPLA3 prosteatotic variant develop more severe hepatic phenotypes [31][32][33] .…”

PNPLA3 gene in liver diseases

“…Since the physiopathology of NAFLD is tightly related to the metabolic syndrome, a link between rs738409[G] and the parameters that define the metabolic syndrome was a likely hypothesis. Indeed, some authors have observed an association between PNPLA3 and insulin resistance [20], and lower fasting triglycerides in severely obese patients and in individuals from Asian descent [21,22]. However, the vast majority of studies have shown that PNPLA3 was not associated with BMI, serum lipid, or glycaemic traits [6,13,23].…”

“…The PNPLA3 rs738409[G] variation displays a strong interaction with the environment. Indeed, as highlighted above, the increased susceptibility to liver damage observed with rs738409[G] occurs predominantly in the presence of a concomitant liver insult (e.g., obesity, alcohol consumption, viral infection) or in association with increased consumption of certain types of fatty acids [21,102,103]. Although rs738409[G] might not be directly associated with all these risk factors, such as every feature of the metabolic syndrome, these phenotypes may, in fact, trigger the impact of PNPLA3 on steatosis and fibrogenesis and the complex relationships among these factors should not be dissociated.…”

Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries

“…The rs738409 variant similarly confers risk for increased histological severity dissociated from its effects on central obesity and IR [157,158] . Its pathogenic role in impaired lipid homeostasis as evidenced by a peripheral decrease in serum triglyceride, total and high-density lipoprotein cholesterol [159,160] is furthermore unmasked in the presence of increased visceral adiposity [161] and impaired glucose tolerance [162] , in addition to being modulated by lifestyle and dietary habits [161,163] . It has further been proposed that lipotoxicity and inflammatory stress resulting from impaired intra-hepatic lipid metabolism and free cholesterol deposition associated with PNPLA3 rs738409 activates dormant hepatic stellate cells (HSCs), leading to increased fibrogenesis.…”