title: Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3.
abstract: OBJECTIVE
  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
  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.
authors: Minerva Foundation Institute for Medical Research, Helsinki, Finland. susanna.lallukka@helsinki.fi
authors: S
authors: S
authors: Lallukka
authors: K
authors: K
authors: Sevastianova
authors: J
authors: J
authors: Perttilä
authors: A
authors: A
authors: Hakkarainen
authors: M
authors: M
authors: Orho-Melander
authors: N
authors: N
authors: Lundbom
authors: V M
authors: VM
authors: Olkkonen
authors: H
authors: H
authors: Yki-Järvinen
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D001823:Body Composition; D005234:Fatty Liver / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications* / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D052242:Adiponectin; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent