Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3
Tóm tắt
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’). Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat (1H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2 ± 0.7 kg/m2; non-obese 26.0 ± 0.4 kg/m2) 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/m2; PNPLA3-148II, 31.2 ± 0.8 kg/m2), 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. 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. 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.
Tài liệu tham khảo
Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523
Younossi ZM, Stepanova M, Afendy M et al (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9:524–530.e1, quiz e60
Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H (2007) Liver fat in the metabolic syndrome. J Clin Endocrinol Metab 92:3490–3497
Kotronen A, Yki-Jarvinen H (2008) Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 28:27–38
Romeo S, Kozlitina J, Xing C et al (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465
He S, McPhaul C, Li JZ et al (2010) A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 285:6706–6715
Kumari M, Schoiswohl G, Chitraju C et al (2012) Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 15:691–702
Sookoian S, Pirola CJ (2011) Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53:1883–1894
Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Kolak M, Westerbacka J, Velagapudi VR et al (2007) Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes 56:1960–1968
Makkonen J, Westerbacka J, Kolak M et al (2007) Increased expression of the macrophage markers and of 11beta-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity. Int J Obes (Lond) 31:1617–1625
Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946
Pietilainen KH, Kannisto K, Korsheninnikova E et al (2006) Acquired obesity increases CD68 and tumor necrosis factor-alpha and decreases adiponectin gene expression in adipose tissue: a study in monozygotic twins. J Clin Endocrinol Metab 91:2776–2781
Pettersson AT, Mejhert N, Jernas M et al (2011) Twist1 in human white adipose tissue and obesity. J Clin Endocrinol Metab 96:133–141
Zeyda M, Stulnig TM (2009) Obesity, inflammation, and insulin resistance: a mini-review. Gerontology 55:379–386
Turer AT, Scherer PE (2012) Adiponectin: mechanistic insights and clinical implications. Diabetologia 55:2319–2326
Kotronen A, Peltonen M, Hakkarainen A et al (2009) Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 137:865–872
Kotronen A, Vehkavaara S, Seppala-Lindroos A, Bergholm R, Yki-Jarvinen H (2007) Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab 293:E1709–E1715
Thomsen C, Becker U, Winkler K, Christoffersen P, Jensen M, Henriksen O (1994) Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging 12:487–495
Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468
Yki-Jarvinen H, Nikkila EA, Kubo K, Foley JE (1986) Assay of glucose transport in human fat cells obtained by needle biopsy. Diabetologia 29:287–290
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505
Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124
Christiansen T, Richelsen B, Bruun JM (2005) Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond) 29:146–150
Westerbacka J, Corner A, Kolak M et al (2008) Insulin regulation of MCP-1 in human adipose tissue of obese and lean women. Am J Physiol Endocrinol Metab 294:E841–E845
Sell H, Eckel J (2007) Monocyte chemotactic protein-1 and its role in insulin resistance. Curr Opin Lipidol 18:258–262
Sosic D, Richardson JA, Yu K, Ornitz DM, Olson EN (2003) Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell 112:169–180
Pettersson AT, Laurencikiene J, Mejhert N et al (2010) A possible inflammatory role of twist1 in human white adipocytes. Diabetes 59:564–571
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792
Ohashi K, Parker JL, Ouchi N et al (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285:6153–6160
Ohashi K, Ouchi N, Matsuzawa Y (2012) Anti-inflammatory and anti-atherogenic properties of adiponectin. Biochimie 94:2137–2142
Fukushima J, Kamada Y, Matsumoto H et al (2009) Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol Res 39:724–738
Kim JY, van de Wall E, Laplante M et al (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117:2621–2637
Westerbacka J, Corner A, Kannisto K et al (2006) Acute in vivo effects of insulin on gene expression in adipose tissue in insulin-resistant and insulin-sensitive subjects. Diabetologia 49:132–140
Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Jarvinen H (2008) Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135:122–130
Sevastianova K, Santos A, Kotronen A et al (2012) Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 96:727–734
Kotronen A, Johansson LE, Johansson LM et al (2009) A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 52:1056–1060
Li JZ, Huang Y, Karaman R et al (2012) Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 122:4130–4144