Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3.

AIMS/HYPOTHESIS: The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD' = PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). METHODS: Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ((1)H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2 ± 0.7 kg/m(2); non-obese 26.0 ± 0.4 kg/m(2)) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m(2); PNPLA3-148II, 31.2 ± 0.8 kg/m(2)), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. RESULTS: Liver fat was similarly increased in obese NAFLD (9.5 ± 1.3% vs 5.1 ± 0.9%, obese vs non-obese, p = 0.007) and PNPLA3 NAFLD (11.4 ± 1.7% vs 5.3 ± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p < 0.001). Fasting serum insulin was higher in the obese than the non-obese group (76 ± 6 vs 47 ± 6 pmol/l, p < 0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60 ± 8 vs 62 ± 5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. CONCLUSIONS/INTERPRETATION: PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.

Non-alcoholic fatty liver disease and risk of type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome ('Metabolic/Obese NAFLD') and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n = 6) or liver enzymes (n = 14). All ultrasonography studies found NAFLD to predict the risk of T2DM independently of age, and in 4 out of 6 studies NAFLD was also a predictor independently of BMI. NAFLD was a predictor of T2DM in all 14 studies where NAFLD was diagnosed by liver enzymes. In 12 of these studies, ALT or AST or GGT were significant predictors of T2DM risk, independently of age and BMI. NAFLD, however, is heterogeneous and may also be caused by common genetic variants. The I148M variant in PNPLA3 and the E167K variant in TM6SF2 are both associated with increased liver fat content, but not features of the metabolic/insulin resistance syndrome. These genetic forms of NAFLD predict NASH and cirrhosis but not T2DM. Taken together these data imply that 'Metabolic/Obese NAFLD' predicts T2DM independently of age and obesity and support the role of hepatic insulin resistance in the pathogenesis of this disease.