Abstract
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.
Highlights
While the role of lipin-1 in regulating lipid metabolism is established, accumulating evidences suggest complex and controversial functional roles of lipin-1 in regulating inflammation process[6,7,8,9,10,11,12,13]
Emerging evidences suggested that ethanol-mediated alterations in lipin-1 functions contribute to abnormalities in the hepatic lipid metabolism and inflammatory processes associated with alcoholic liver disease (ALD) in rodents and human[9,10,14,15,16,17,18]
We provided novel evidence demonstrating that the protective effects of myeloid cell-specific lipin-1 deficiency against inflammation and liver injury in the ethanol-exposed mice were mediated, at least in part, through coordinated elevation and stimulation of two prominent endocrine hormones, adipose-derived adiponectin and gut-derived fibroblast growth factor (FGF) 15, and their hepatic signaling
Summary
While the role of lipin-1 in regulating lipid metabolism is established, accumulating evidences suggest complex and controversial functional roles of lipin-1 in regulating inflammation process[6,7,8,9,10,11,12,13]. Upon Toll-Like-Receptor (TLR) stimulation of macrophages from humans or lipin-1-deficient mice, the generation of proinflammatory cytokines known to involve in inflammatory process was reduced[12]. We discovered that hepatocyte-specific lipin-1 ablation exacerbated inflammation and aggravated the development and progression of experimental steatohepatitis in mice after ethanol challenge, suggesting that hepatocyte-specific lipin-1 exerts anti-inflammatory properties in alcoholic steatohepatitis[9] It remains unknown whether and how myeloid cell-specific lipin-1 influences alcoholic steatosis, inflammatory conditions and liver injury in vivo. We provided novel evidence demonstrating that the protective effects of myeloid cell-specific lipin-1 deficiency against inflammation and liver injury in the ethanol-exposed mice were mediated, at least in part, through coordinated elevation and stimulation of two prominent endocrine hormones, adipose-derived adiponectin and gut-derived fibroblast growth factor (FGF) 15, and their hepatic signaling
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