The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls

Abstract

BackgroundReduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls.MethodsTo this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery.ResultsAdiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features.ConclusionsThe I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

“…Thus, PNPLA3 rs738409 has been functionally linked to increased levels of circulating pro-inflammatory mediator intracellular adhesion molecule 1 (ICAM-1) [27], which is also overexpressed in human HCC stem cells and circulating HCC tumor cells [28]. Furthermore, in patients with NAFLD PNPLA3rs738409 G allele was found to be associated with decreased levels of adiponectin which has important anti-inflammatory, anti-fibrotic and anti-carcinogenic properties [29]. Recent data in cell culture and mice xenografts also suggest an effect of PNPLA3 rs738409 on the activation of the interleukin (IL)-6-Janus kinase (JAK2)/Signal Transducers and Activators of Transcription (STAT3) pathway via fatty acid-mediated inflammation [30].…”

“…For preparation of genotyping, DNA samples were evaluated by gel electrophoresis and adjusted to [20][21][22][23][24][25][26][27][28][29][30] ng/µl DNA content using the Picogreen fluorescent dye (Molecular Probes -Invitrogen, Carlsbad, Ca, USA) on a robotic platform using TECAN liquid handling equipment. One microliter of genomic DNA was amplified with the GenomiPhi (Amersham, Uppsala, Sweden) whole genome amplification kit and fragmented at 99°C for three minutes.…”

Adiponectin serum level changes and its dynamic relationship with hepatitis C during viral clearance

“…Valenti et al have showed that rs738409 single nucleotide polymorphism of PNPLA3, encoding for a protein variant (I148M), influences hepatic triglycerides accumulation, the susceptibility to fibrosis, the response to antiviral treatment and may represent a genetic determinant of adiponectin levels in CHC. 17,18 The relevance of genetics in the development of liver steatosis and adiponectin changes in CHC is confirmed in this study by the description of the role of IFNL3 genotype CC. The significant impact of relatively frequent genetic variants, such as the PNPLA3 I148M or the IFNLA3 genotype CC, suggests some important considerations: 1) genetic variants affecting tissue-specific proteins, like the adipokines, may have both localized or systemic effects, involving apparently separate systems, such as adipose tissue, liver, and immune system, and providing a mechanistic link to understand the pathogenesis of several multifactorial disorders; 2) in the future, diagnosis and management of liver disorders should take into account the genetic background of each patient, since this could have serious consequences on the evolution and the prognosis of the disease.…”

Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease

“…The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Therefore, in carriers of the 1148M PNPLA3 variant, modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis [44] .…”