Lipin proteins including Lipin 1–3 act as transcriptional co-activators and phosphatidic acid phosphohydrolase enzymes,which play crucial roles in lipid metabolism.However,little is known about the function of Lipin3...Lipin proteins including Lipin 1–3 act as transcriptional co-activators and phosphatidic acid phosphohydrolase enzymes,which play crucial roles in lipid metabolism.However,little is known about the function of Lipin3 in triglyceride(TG)metabolism.Here,we identified a novel mutation(NM_001301860:p.1835A>T/p.D612V)of Lipin3 in a large family with hypertriglyceridemia(HTG)and obesity through whole-exome sequencing and Sanger sequencing.Functional studies revealed that the novel variant altered the half-life and stability of the Lipin3 protein.Hence,we generated Lipin3 heterozygous knockout(Lipin3-heKO)mice and cultured primary hepatocytes to explore the pathophysiological roles of Lipin3 in TG metabolism.We found that Lipin3-heKO mice exhibited obvious obesity,HTG,and non-alcoholic fatty liver disorder.Mechanistic study demonstrated that the haploinsufficiency of Lipin3 in primary hepatocytes may induce the overexpression and abnormal distribution of Lipin1 in cytosol and nucleoplasm.The increased expression of Lipin1 in cytosol may contribute to TG anabolism,and the decreased Lipin1 in nucleoplasm can reduce PGC1α,further leading to mitochondrial dysfunction and reduced TG catabolism.Our study suggested that Lipin3 was a novel disease-causing gene inducing obesity and HTG.We also established a relationship between Lipin3 and mitochondrial dysfunction.展开更多
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has ...Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82170598,82000427,and 81970403)the Key Research and Development Program of Hunan Province(No.2022sk2034)the Natural Science Foundation of Hunan Province(Nos.2022JJ30058 and 2023JJ20078).
文摘Lipin proteins including Lipin 1–3 act as transcriptional co-activators and phosphatidic acid phosphohydrolase enzymes,which play crucial roles in lipid metabolism.However,little is known about the function of Lipin3 in triglyceride(TG)metabolism.Here,we identified a novel mutation(NM_001301860:p.1835A>T/p.D612V)of Lipin3 in a large family with hypertriglyceridemia(HTG)and obesity through whole-exome sequencing and Sanger sequencing.Functional studies revealed that the novel variant altered the half-life and stability of the Lipin3 protein.Hence,we generated Lipin3 heterozygous knockout(Lipin3-heKO)mice and cultured primary hepatocytes to explore the pathophysiological roles of Lipin3 in TG metabolism.We found that Lipin3-heKO mice exhibited obvious obesity,HTG,and non-alcoholic fatty liver disorder.Mechanistic study demonstrated that the haploinsufficiency of Lipin3 in primary hepatocytes may induce the overexpression and abnormal distribution of Lipin1 in cytosol and nucleoplasm.The increased expression of Lipin1 in cytosol may contribute to TG anabolism,and the decreased Lipin1 in nucleoplasm can reduce PGC1α,further leading to mitochondrial dysfunction and reduced TG catabolism.Our study suggested that Lipin3 was a novel disease-causing gene inducing obesity and HTG.We also established a relationship between Lipin3 and mitochondrial dysfunction.
基金Supported by NIAAA funds R01 AA020518National Center for Research Resources No.5P20RR021940 and No.T32ES007079Williams JA and Manley S are recipients of the Biomedical Research Training Program Fellowship from University of Kansas Medical Center
文摘Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
