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

Abstract

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. Keywords

Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH)

“…However, hepatitis C virus (HCV)-related steatosis may not be affected by polymorphisms, as HCV itself can induce hepatic lipid accumulation [21,22]. Not all patients with progressive NASH have the PNPLA3 risk allele; thus, differences in the characteristics of PNPLA3 risk allele bearing- and non-bearing-NAFLD patients have been demonstrated [23]. PNPLA3-related NAFLD is not characterized by features typical of metabolic syndrome, including hyperinsulinemia, hypertriglyceridemia and low HDL-cholesterol levels [24].…”

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…A recent review of PNPLA3 polymorphism suggested that PNPLA3 is more likely to influence lipid content and liver disease severity but not insulin resistance [95] . Lallukka et al [97] demonstrated that NAFLD patients with polymorphism of PNPLA3 is not characterised by adipose tissue inflammation, insulin resistance and features of the metabolic syndrome such as hyperinsulinaemia, hypertriacylglycerolaemia and a low HDL-cholesterol concentration. Despite the less clear relationship in insulin resistance, the severity of NAFLD has been proven to be related to the PNPLA3 in T2DM populations.…”

The Risk of Heart Failure and Cardiometabolic Complications in Obesity May Be Masked by an Apparent Healthy Status of Normal Blood Glucose

“…During macrophage infiltration, the M1 phenotype is stimulated by different chemokines including macrophage inflammatory protein-1 alpha ((MIP-1 α ), chemokine (C-C motif) ligand-3 (CCL3)) and macrophage chemoattractant protein-1 ((MCP-1) [9], chemokine (C-C motif ligand-2 (CCL2)) [9]. The activation of the macrophage M1 phenotype is generally associated with elevated levels of proinflammatory cytokines including TNF- α , IL-6, and IL-1 β [10–12]. Moreover, the levels of macrophage M1 phenotype, MCP-1, TNF- α , IL-6, and IL-1 β are elevated in obesity and insulin resistance [9, 10, 13], and these factors play a major pathophysiological role in heart failure [4].…”

“…The activation of the macrophage M1 phenotype is generally associated with elevated levels of proinflammatory cytokines including TNF- α , IL-6, and IL-1 β [10–12]. Moreover, the levels of macrophage M1 phenotype, MCP-1, TNF- α , IL-6, and IL-1 β are elevated in obesity and insulin resistance [9, 10, 13], and these factors play a major pathophysiological role in heart failure [4]. In obesity, markers of heart failure such as osteopontin [14] and osteoprotegerin [15] are elevated [16, 17].…”