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PNPLA3 I148M Variant Influences Circulating Retinol in Adults with Nonalcoholic Fatty Liver Disease or Obesity.

ABSTRACT: Retinol is a lipid-soluble essential nutrient that is stored as retinyl esters in lipid droplets of hepatic stellate cells. Patatin-like phospholipase domain-containing 3 (PNPLA3), through its retinyl-palmitate lipase activity, releases retinol from lipid droplets in hepatic stellate cells in vitro and ex vivo. We have shown that the genetic variant I148M (rs738409) reduces the PNPLA3 retinyl-palmitate lipase activity.The aim of the present genetic association study was to test whether overweight/obese carriers of the PNPLA3 148M mutant allele had lower circulating concentrations of retinol than individuals who are homozygous for the 148I allele.PNPLA3 I148M (rs738409) was genotyped by Taqman assay in 76 overweight/obese individuals [BMI (kg/m(2)) ?25; mean ± SD age: 59.7 ± 11.4 y; male gender: 70%] with a histologic diagnosis of nonalcoholic fatty liver disease (NAFLD; namely the Milan NAFLD cohort) and in 413 obese men (BMI ?30; mean ± SD age: 57.1 ± 4.9 y) from the ?-Tocopherol, ?-Carotene Cancer Prevention (ATBC) Study. Serum concentrations of retinol and ?-tocopherol were measured by HPLC in both cohorts. ?-Carotene concentrations in the ATBC study were measured by using HPLC.The PNPLA3 148M mutant allele was associated with lower fasting circulating concentrations of retinol (? = -0.289, P = 0.03) in adults with NAFLD (Milan NAFLD cohort). The PNPLA3 148M mutant allele was also associated with lower fasting circulating concentrations of retinol in adults with a BMI ?30 (ATBC study; ? = -0.043, P = 0.04).We showed for the first time, to our knowledge, that carriers of the PNPLA3 148M allele with either fatty liver plus obesity or obesity alone have lower fasting circulating retinol concentrations.

SUBMITTER: Mondul A

PROVIDER: S-EPMC4516767 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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PNPLA3 I148M Variant Influences Circulating Retinol in Adults with Nonalcoholic Fatty Liver Disease or Obesity.

Mondul Alison A Mancina Rosellina M RM Merlo Andrea A Dongiovanni Paola P Rametta Raffaela R Montalcini Tiziana T Valenti Luca L Albanes Demetrius D Romeo Stefano S

The Journal of nutrition 20150701 8

<h4>Background</h4>Retinol is a lipid-soluble essential nutrient that is stored as retinyl esters in lipid droplets of hepatic stellate cells. Patatin-like phospholipase domain-containing 3 (PNPLA3), through its retinyl-palmitate lipase activity, releases retinol from lipid droplets in hepatic stellate cells in vitro and ex vivo. We have shown that the genetic variant I148M (rs738409) reduces the PNPLA3 retinyl-palmitate lipase activity.<h4>Objective</h4>The aim of the present genetic associatio ...[more]

PMID: 26136587

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Project description: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.

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PNPLA3 I148M Variant Influences Circulating Retinol in Adults with Nonalcoholic Fatty Liver Disease or Obesity.

Publications

PNPLA3 I148M Variant Influences Circulating Retinol in Adults with Nonalcoholic Fatty Liver Disease or Obesity.

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