Expression and Characterization of a PNPLA3 Protein Isoform (I148M) Associated with Nonalcoholic Fatty Liver Disease

Huang, Yunxin; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1074/jbc.m111.290114

Cited by 265 publications

(315 citation statements)

References 23 publications

(40 reference statements)

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“…PNPLA3 exhibits predominantly hydrolase (lipase) activity in vitro against triglycerides (TG) and retinyl esters in hepatic stellate cells [76,[78][79][80] (Fig. 1).…”

Section: Reviewmentioning

confidence: 99%

“…1). Among TG, PNPLA3 has a higher enzymatic activity against those containing monounsaturated and polyunsaturated fatty acids [78,81].…”

Section: Reviewmentioning

confidence: 99%

“…In mice, He et al showed that the I148M substitution seems to abolish hydrolase activity by reducing substrate access to the enzyme's active site and so promotes TG accumulation suggesting a loss of function [76]. Using recombinant human PNPLA3 and PNPLA3-I148M proteins, studies showed that fatty acid release increased linearly with increased TG and was reduced by the I148M substitution, indicating a loss of function [78,82]. Nevertheless, He et al also observed that an overexpression of wild-type (WT) PNPLA3 in mouse liver created no obvious phenotype and, more specifically, did not reduce hepatic TG content [76].…”

Section: Reviewmentioning

confidence: 99%

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PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

220

196

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“…PNPLA3 exhibits predominantly hydrolase (lipase) activity in vitro against triglycerides (TG) and retinyl esters in hepatic stellate cells [76,[78][79][80] (Fig. 1).…”

Section: Reviewmentioning

confidence: 99%

“…1). Among TG, PNPLA3 has a higher enzymatic activity against those containing monounsaturated and polyunsaturated fatty acids [78,81].…”

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

See 1 more Smart Citation

PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

220

196

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“…In vitro studies using recombinant purified human PNPLA3 have shown that the wild-type enzyme hydrolyzes triglycerides and that the I148M substitution abolishes this activity (9). These data suggested that the I148M substitution is a loss-of-function mutation impairing triglyceride hydrolysis.…”

Section: IImentioning

confidence: 99%

Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

et al. 2013

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We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3 I148M gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3 I148M gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3 148MM/148MI compared with the PNPLA3 148II group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulinresistant. Liver fat was similarly increased in obese and PNPLA3 148MM/148MI groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3 I148M versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

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“…A single nucleotide polymorphism (SNP) in the PNPLA3 gene, i.e., rs738409 C>G, results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3 2. This common variant represents a missense mutation associated with a loss‐of‐function of the hydrolase activity of the enzyme, promoting triglyceride accumulation in hepatocytes, impaired retinol synthesis in hepatic stellate cells, formation of larger lipid droplets, and reduced secretion of triglyceride‐rich very low‐density lipoprotein (VLDL) both in vitro and in vivo (reviewed in Trepo et al5).…”

mentioning

confidence: 99%

Patatin‐like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events

Rüschenbaum

Schwarzkopf

Friedrich‐Rust

et al. 2018

Hepatology Communications

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Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin‐like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss‐of‐function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well‐established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low‐density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. (Hepatology Communications 2018;2:798‐806)

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Expression and Characterization of a PNPLA3 Protein Isoform (I148M) Associated with Nonalcoholic Fatty Liver Disease

Cited by 265 publications

References 23 publications

PNPLA3 gene in liver diseases

PNPLA3 gene in liver diseases

Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

Patatin‐like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events

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