期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 18, 页码 6958-6968出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.002333
关键词
triglyceride; phospholipid; phosphatidylglycerol; polyunsaturated fatty acid (PUFA); lipase; hepatic steatosis
资金
- NIGMS, National Institutes of Health (NIH) [K01-GM109317]
- NIDDK, NIH [R01-DK090066]
- NHLBI Grant [P01 HL20948]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL020948] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK090066] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K01GM109317] Funding Source: NIH RePORTER
Fatty liver disease (FLD) is a burgeoning health problem. A missense variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) confers susceptibility to FLD, although the mechanism is not known. To glean first insights into the physiological function of PNPLA3, we performed detailed lipidomic profiling of liver lysates and lipid droplets (LDs) from WT and Pnpla3(-/-) (KO) mice and from knock-in (ki) mice expressing either the 148M variant (IM-ki mice) or a variant (S47A) that renders the protein catalytically inactive (SA-ki mice). The four strains differed in composition of very-long-chain polyunsaturated fatty acids (vLCPUFA) in hepatic LDs. In the LDs of IM-ki mice, vLCPUFAs were depleted from triglycerides and enriched in phospholipids. Conversely, vLCPUFAs were enriched in triglycerides and depleted from phospholipids in SA-ki and Pnpla3(-/-) mice. Release of vLCPUFAs from hepatic LDs incubated ex vivo was increased in droplets from IM-ki mice and decreased from droplets isolated from Pnpla3(-/-) and SA-ki mice relative to those of WT mice. Thus, the physiological role of PNPLA3 appears to be to remodel triglycerides and phospholipids in LDs, perhaps to accommodate changes in LD size in response to feeding. Because SA-ki and IM-ki both cause FLD and yet have opposite effects on the lipidomic profile of LDs, we conclude that the FLD associated with genetic variation in PNPLA3 is not related to the enzyme's role in remodeling LD lipids.
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