A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis

By Shaoqing He, Christopher M McPhaul, J. Li, R. Garuti, Lisa N. Kinch, Nick V. Grishin, Jonathan C. Cohen, Helen H. Hobbs. Journal of Biological Chemistry, 2009

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Obesity and insulin resistance are associated with deposition of triglycerides in tissues other than adipose tissue. Previously, we showed that a missense mutation (I148M) in PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is associated with increased hepatic triglyceride content in humans. Here we examined the effect of the I148M substitution on the enzymatic activity and cellular location of PNPLA3. Structural modeling predicted that the substitution of methionine for isoleucine at residue 148 would restrict access of substrate to the catalytic serine at residue 47. In vitro assays using recombinant PNPLA3 partially purified from Sf9 cells confirmed that the wild type enzyme hydrolyzes emulsified triglyceride and that the I148M substitution abolishes this activity. Expression of PNPLA3-I148M, but not wild type PNPLA3, in cultured hepatocytes or in the livers of mice increased cellular triglyceride content. Cell fractionation studies revealed that ∼90% of wild type PNPLA3 partitioned between membranes and lipid droplets; substitution of isoleucine for methionine at position 148 did not alter the subcellular distribution of the protein. These data are consistent with PNPLA3-I148M promoting triglyceride accumulation by limiting triglyceride hydrolysis.

Subfields: Biochemistry, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ea1146060a7c468ed31511c67fcab47230f43410

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Citations in the corpus

Non Alcoholic Fatty Liver Disease, Hepatic Insulin Resistance and Type 2 Diabetes (2014, background): “However, overexpression of PNPLA3 did not alter liver lipid content.(83,84) In contrast, knockdown of hepatic and adipose tissue PNPLA3 expression in rats with ASOs actually reduced hepatic TAG and DAG content and prevented lipid-induced hepatic insulin resistance when adult rats were fed an HFD for”
Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links (2012, positive): “Adenoviral overexpression of the mutant gene in mice increases lipid droplet size and triglyceride accumulation in vivo, consistent with the human data (He et al., 2010).”
Homozygosity for the patatin‐like phospholipase‐3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease (2010, background): “Recently, it was reported that the 148M adiponutrin allele is a loss-offunction variant that predisposes an individual to steatosis by decreasing triglyceride hydrolysis in hepatocytes.(20) However, although the adiponutrin genotype has previously been reported to be associated with steatosis severi”
Peroxisome Proliferator-Activated Receptor Alpha Target Genes (2010, background): “Which other lipases importantly contribute to intracellular lipolysis of hepatic TG stores remains unclear, but lipases active in adipocytes likely play a role, including Ces3, Lipe, Pnpla2, Mgll, and perhaps Pnpla3 [195–200].”
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 (2011, background): “The current meta-analysis is useful to clearly understand the magnitude of the effect of rs738409 on the histological severity of NAFLD, which is far beyond the small magnitude observed for common variants on complex traits,(29) and may be explained by the nonsynonymous nature of the polymorphism th”
Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits (2011, background): “hepatic steatosis by preventing breakdown of triglycerides, as recently shown for PNPLA3(I148M) [33].”
Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol (2011, background): “Finally, the raised liver fat levels despite metabolic normality in some controls can be considered in the light of the recent description of the PNPLA3 gene [46].”