Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice

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.

Endocrine Adiponectin‐FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury

“…12,13 Accordingly, the serum level of FGF15 was reduced in these mice after ethanol administration. 12,13 The lower expression of ileum FGF15 in the ethanol-fed mice could potentially be mediated via an increased absorption of bile acids into the portal circulation. 24 As discussed above, signaling of FGF15/19 requires FGFR4/β-Klotho in liver.…”

“…5 When mice were treated with recombinant FGF19, adipose adiponectin mRNA levels were significantly increased, while hepatic mRNA of CYP7A1, an indicator of FGF15/19 signaling, was decreased. 12 Mice treated with recombinant globular adiponectin had significantly higher ileum FGF15 mRNA levels, but unexpectedly, increased levels of hepatic CYP7A1 mRNA. 12 These results suggested a potential regulatory link between adiponectin and CYP7A1.…”

“…12 Mice treated with recombinant globular adiponectin had significantly higher ileum FGF15 mRNA levels, but unexpectedly, increased levels of hepatic CYP7A1 mRNA. 12 These results suggested a potential regulatory link between adiponectin and CYP7A1. Additionally, FGF15 null mice demonstrated significantly lower adipose adiponectin mRNA levels and higher hepatic Cyp7a1 mRNA levels.…”

“…This unique endocrine adiponectin-FGF15/19 axis is a pivotal regulator of the inflammation process, bile acid homeostasis, and lipid metabolism in liver. 5,12,13 …”

“…Additionally, FGF15 null mice demonstrated significantly lower adipose adiponectin mRNA levels and higher hepatic Cyp7a1 mRNA levels. 12 In FGFR4 knockout mice, FGF15/19 was concurrently elevated with adiponectin leading to increased insulin sensitivity, improved glucose metabolism, and body weight reduction while on a high fat diet. 5 These results demonstrated that adiponectin and FGF15/19 reciprocally regulate each other in mice and that the adiponectin-FGF15/19 axis participates in various signaling cascades, including inflammation and lipid metabolism pathways.…”