Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice.
Lipin-1 is a phosphatidate phosphohydrolase (PAP) required for the generation of diacylglycerol during glycerolipid synthesis, and exhibits dual functions in the regulation of lipid metabolism. Lipin-1 has been implicated in the pathogenesis of alcoholic liver disease (ALD). In the present study, we assessed lipin-1 function in myeloid cells in ALD using a myeloid cell-specific lipin-1 knockout (mLipin-1KO) mouse model. Utilizing the Gao-binge ethanol feeding protocol, matched mLipin-1KO mice and littermate loxP control (WT) mice were pair-fed with either an ethanol-containing diet or an ethanol-free diet (control). Surprisingly, deletion of lipin-1 in myeloid cells dramatically attenuated liver inflammatory responses and ameliorated liver injury that would normally occur following the ethanol feeding protocol, but slightly exacerbated the ethanol-induced steatosis in mice. Mechanistically, myeloid cell-specific lipin-1 deficiency concomitantly increased the fat-derived adiponectin and ileum-derived fibroblast growth factor (FGF) 15. In concordance with concerted elevation of circulating adiponectin and FGF15, myeloid cell-specific lipin-1 deficiency diminished hepatic nuclear factor kappa B (NF-κB) activity, limited liver inflammatory responses, normalized serum levels of bile acids, and protected mice from liver damage after ethanol challenge. Our novel data demonstrate that myeloid cell-specific deletion of lipin-1 ameliorated inflammation and alcoholic hepatitis in mice via activation of endocrine adiponectin-FGF15 signaling.
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Jiayou
J
Wang
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Chunki
C
Kim
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Alvin
A
Jogasuria
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Yoonhee
Y
Han
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.|Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Xudong
X
Hu
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Jiashin
J
Wu
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.|Department of Liver Diseases, Guangdong Hospital of Traditional Chinese Medicine in Zhuhai, Zhuhai, China.
Hong
H
Shen
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Roman
R
Chrast
Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, USA.
Brian N
BN
Finck
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, USA.
Min
M
You
D052242:Adiponectin / Q000097:blood*; D000818:Animals; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000097:blood*; D055786:Gene Knockout Techniques; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency*; D009928:Organ Specificity; D010711:Phosphatidate Phosphatase / Q000172:deficiency*; D015398:Signal Transduction
D052242:Adiponectin; C499919:Adipoq protein, mouse; D016328:NF-kappa B; D009687:Nuclear Proteins; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase
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