Patatin-like phospholipase domain–containing protein 3 promotes transfers of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets

Mitsche, Michael A.; Hobbs, Helen H.; Cohen, Jonathan C.

doi:10.1074/jbc.aac118.004058

Cited by 13 publications

(11 citation statements)

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“…In human liver samples, concentrations of polyunsaturated PCs were significantly decreased, while TGs were increased in the livers of homozygous carriers of the PNPLA3-I148M variant as compared with noncarriers ( Figure 6). These data closely resemble those of KI mice expressing a catalytically inactive PNPLA3 variant (PNPLA3-S47A-KI mice) but oppose those characterizing PNPLA3-148M-KI mice (7). In these mice, very long-chain PUFAs are enriched in TGs and depleted in phospholipids.…”

Section: Discussionsupporting

confidence: 60%

“…monounsaturated TGs (5). The human lipidomic data of NAFLD in PNPLA3 variant carriers closely resemble the hepatic lipidomic profile of PNPLA3-KO mice (6,7). In the latter study, PNPLA3 was proposed to act as a transacylase transferring PUFAs from TG to lysophospholipids or as a TG hydrolase hydrolyzing PUFAs from TGs in a remodeling pathway for lipid droplet phospholipids (7).…”

Section: Introductionmentioning

confidence: 91%

“…However, data from mouse models are not easy to reconcile with the human data. PNPLA3-KO mice accumulate polyunsaturated TGs but do not develop hepatic steatosis (6)(7)(8). Opposite to humans and knock-in (KI) mice expressing a catalytically inactive PNPLA3 (PNPLA3-S47A-KI), PUFAs are depleted in hepatic TGs in I148M-KI mice -i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Opposite to humans and knock-in (KI) mice expressing a catalytically inactive PNPLA3 (PNPLA3-S47A-KI), PUFAs are depleted in hepatic TGs in I148M-KI mice -i.e. in mice in which the I148M has been introduced to the endogenous mouse PNPLA3 gene (7). Mouse PNPLA3 is approximately 68% homologous with human PNPLA3 (9).…”

Section: Introductionmentioning

confidence: 99%

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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Nick²,

et al. 2019

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Nick²,

et al. 2019

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“…This finding is consistent with Chamoun et al (25) and raises the possibility that CGI-58 acts as a cofactor for PNPLA3, as well as ATGL. However, given that inactivation of PNPLA3 in mice results in specific accumulation of very-long-chain polyunsaturated FA-containing TG, (34) but not bulk TG, (11,12) in the liver, and that overexpression of PNPLA3 decreases the same TG species (34) without affecting hepatic TG content, (9) we think that the depletion of LD in cultured cells is caused by the supraphysiological co-expression of CGI-58 and PNPLA3.…”

Section: Discussionmentioning

confidence: 92%

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

et al. 2019

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A variant (148M) in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) is a major risk factor for fatty liver disease. Despite its clinical importance, the pathogenic mechanism linking the variant to liver disease remains poorly defined. Previously, we showed that PNPLA3(148M) accumulates to high levels on hepatic lipid droplets (LDs). Here we examined the effect of that accumulation on triglyceride (TG) hydrolysis by adipose triglyceride lipase (ATGL), the major lipase in the liver. As expected, overexpression of ATGL in cultured hepatoma (HuH‐7) cells depleted the cells of LDs, but unexpectedly, co‐expression of PNPLA3(wild type [WT] or 148M) with ATGL inhibited that depletion. The inhibitory effect of PNPLA3 was not caused by the displacement of ATGL from LDs. We tested the hypothesis that PNPLA3 interferes with ATGL activity by interacting with its cofactor, comparative gene identification‐58 (CGI‐58). Evidence supporting such an interaction came from two findings. First, co‐expression of PNPLA3 and CGI‐58 resulted in LD depletion in cultured cells, but expression of PNPLA3 alone did not. Second, PNPLA3 failed to localize to hepatic LDs in liver‐specific Cgi ‐ 58 knockout (KO) mice. Moreover, overexpression of PNPLA3(148M) increased hepatic TG levels in WT, but not in Cgi ‐ 58 KO mice. Thus, the pro‐steatotic effects of PNPLA3 required the presence of CGI‐58. Co‐immunoprecipitation and pulldown experiments in livers of mice and in vitro using purified proteins provided evidence that PNPLA3 and CGI‐58 can interact directly. Conclusion: Taken together, these findings are consistent with a model in which PNPLA3(148M) promotes steatosis by CGI‐58‐dependent inhibition of ATGL on LDs.

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Pathophysiologie: Genetik

Weber

Lammert

2022

Nicht-Alkoholische Fettlebererkrankung

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Patatin-like phospholipase domain–containing protein 3 promotes transfers of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets

Cited by 13 publications

References 0 publications

Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

Pathophysiologie: Genetik

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