Abstract
Background and AimNon-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals.MethodsThe rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (n total = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR).ResultsThe case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = −9.9% [−14.4%;−4.0% (95% CI)], p = 5.1×10−5) and fasting total cholesterol (β = −0.2 mmol/l [−0.3;−0.01 mmol/l(95% CI)], p = 1.5×10−4). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele.ConclusionOur findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as the deposition of fat in hepatocytes exceeding 5–10% of the liverweight, not caused by excessive alcohol consumption [1]
Regulation of hepatic TAG synthesis and degradation is influenced by insulin levels and by circulating glucose levels via the liver X-receptor (LXR) which regulates carbohydrate response element binding protein (ChREBP), the sterol response element binding protein-1c (SREBP-1c) and downstream enzymes involved in fatty acid and TAG synthesis [10]
Among 4,306 individuals with normal glucose-tolerance (NGT), the rs738409 G-allele was associated with fasting plasma glucose levels (b = 20.4% [20.7%; 20.01%], p = 0.04)
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as the deposition of fat in hepatocytes exceeding 5–10% of the liverweight, not caused by excessive alcohol consumption [1]. NAFLD is often present in obese individuals and liver fat content is linearly correlated to components of the metabolic syndrome, e.g. increased fasting plasma glucose- and fasting serum triglyceridelevels and increased waist circumference [3,4]. Accumulation of fat in the liver is associated with hepatic insulin resistance [5,6]. Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals
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