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Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.

ABSTRACT: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH).We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis.PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ? 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3).The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.

SUBMITTER: Valenti L

PROVIDER: S-EPMC3374985 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.

Valenti Luca L Maggioni Paolo P Piperno Alberto A Rametta Raffaela R Pelucchi Sara S Mariani Raffaella R Dongiovanni Paola P Fracanzani Anna Ludovica AL Fargion Silvia S

World journal of gastroenterology 20120601 22

<h4>Aim</h4>To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH).<h4>Methods</h4>We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d ...[more]

PMID: 22719190

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Project description:Background and aimsThe mechanisms by which the I148M mutant variant of the patatin-like phospholipase domain-containing 3 (PNPLA3I148M ) drives development of nonalcoholic steatohepatitis (NASH) are not known. The aim of this study was to obtain insights on mechanisms underlying PNPLA3I148M -induced acceleration of NASH.Approach and resultsHepatocyte-specific overexpression of empty vector (luciferase), human wild-type PNPLA3, or PNPLA3I148M was achieved using adeno-associated virus 8 in a diet-induced mouse model of nonalcoholic fatty liver disease followed by chow diet or high-fat Western diet with ad libitum administration of sugar in drinking water (WDSW) for 8 weeks. Under WDSW, PNPLA3I148M overexpression accelerated steatohepatitis with increased steatosis, inflammation ballooning, and fibrosis (P < 0.001 versus other groups for all). Silencing PNPLA3I148M after its initial overexpression abrogated these findings. PNPLA3I148M caused 22:6n3 docosahexanoic acid depletion and increased ceramides under WDSW in addition to increasing triglycerides and diglycerides, especially enriched with unsaturated fatty acids. It also increased oxidative stress and endoplasmic reticulum stress. Increased total ceramides was associated with signature of transducer and activator of transcription 3 (STAT3) activation with downstream activation of multiple immune-inflammatory pathways at a transcriptomic level by network analyses. Silencing PNPLA3I148M reversed STAT3 activation. Conditioned media from HepG2 cells overexpressing PNPLA3I148M increased procollagen mRNA expression in LX2 cells; this was abrogated by hepatocyte STAT3 inhibition.ConclusionsUnder WDSW, PNPLA3I148M overexpression promotes steatosis and NASH by metabolic reprogramming characterized by increased triglycerides and diglycerides, n3 polyunsaturated fatty acid depletion, and increased ceramides with resultant STAT3 phosphorylation and downstream inflammatory pathway activation driving increased stellate cell fibrogenic activity.

Project description:At least eight families of mammalian patatin-like phospholipase domain-containing proteins (PNPLA) (E.C. 3.1.1.3) catalyse the hydrolysis of triglycerides, including PNPLA4 (alternatively PLPL4 or GS2), which also acts as a retinol transacylase and participates in retinol-ester metabolism in the body. Bioinformatic methods were used to predict the amino acid sequences, secondary and tertiary structures and gene locations for PNPLA4 genes and encoded proteins using data from several vertebrate genome projects. PNPLA4 genes were located on the X-chromosome for the eutherian mammalian genomes examined. Opossum (marsupial), chicken, anole lizard, clawed toad, zebrafish and lancelet PNPLA4 genes were also identified. Most vertebrate PNPLA4 genes typically contained six coding exons whereas the lancelet PNPLA4 gene contained five coding exons. PNPLA4 subunits were the smallest among the PNPLA-like proteins examined containing 252–255 residues, shared >64 % sequence identities and key amino acid residues and predicted motifs, including ‘patatin’ (residues 6–176); putative catalytic dyad active site residues, Ser43 and Asp163; oxy-anion ‘hole’ residues (10–15); and conserved serine residues, which may perform structural roles for this enzyme. Predicted tertiary structures for PNPLA4 ‘patatin’ were similar to those reported for potato ‘patatin’, suggesting that it is strongly conserved during evolution. Human PNPLA4 contained a CpG49 island within the gene promoter, a miRNA-186 binding site within the mRNA 3′-noncoding region for the PNPLA4b isoform and exhibited wide tissue expression at a higher than average level. These and previous studies of vertebrate PNPLA-like gene families have suggested that PNPLA4 is an ancient gene in evolution which has resulted from a duplication of an ancestral invertebrate ATGL-like gene (encoding adipose triglyceride lipase). Electronic supplementary material The online version of this article (doi:10.1007/s13205-012-0063-7) contains supplementary material, which is available to authorized users.

Dataset Information

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.

Publications

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.

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