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Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.

ABSTRACT: The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, which has a central modulatory role in multiple proinflammatory signaling pathways involved in the pathomechanism of ALD. Using mouse disease models that represent various phases in the progression of human ALD, we found that alcohol, in all of these models, induced SYK activation in the liver, both in hepatocytes and liver mononuclear cells. Furthermore, significant SYK activation also occurred in liver samples and peripheral blood mononuclear cells of patients with ALD/alcoholic hepatitis compared to controls. Functional inhibition of SYK activation in vivo abrogated alcohol-induced hepatic neutrophil infiltration, resident immune cell activation, as well as inflammasome and extracellular signal-regulated kinase 1 and 2-mediated nuclear factor kappa B activation in mice. Strikingly, inhibition of SYK activation diminished alcohol-induced hepatic steatosis and interferon regulatory factor 3-mediated apoptosis.Our data demonstrate a novel, functional, and multicellular role for SYK phosphorylation in modulating immune cell-driven liver inflammation, hepatocyte cell death, and steatosis at different stages of ALD. These novel findings highlight SYK as a potential multifunctional target in the treatment of alcoholic steatohepatitis. (Hepatology 2016;64:1057-1071).

SUBMITTER: Bukong TN

PROVIDER: S-EPMC5033691 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.

Bukong Terence N TN Iracheta-Vellve Arvin A Saha Banishree B Ambade Aditya A Satishchandran Abhishek A Gyongyosi Benedek B Lowe Patrick P Catalano Donna D Kodys Karen K Szabo Gyongyi G

Hepatology (Baltimore, Md.) 20160722 4

<h4>Unlabelled</h4>The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, which has a central modulatory role in multiple proinflammatory signaling ...[more]

PMID: 27302565

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Project description:Background & aimsPhospholipase D1 (PLD1), a phosphatidylcholine-hydrolysing enzyme, is involved in cellular lipid metabolism. However, its involvement in hepatocyte lipid metabolism and consequently non-alcoholic fatty liver disease (NAFLD) has not been explicitly explored.MethodsNAFLD was induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) and littermate Pld1 flox/flox (Pld1-Flox) control mice feeding a high-fat diet (HFD) for 20 wk. Changes of the lipid composition in the liver were compared. Alpha mouse liver 12 (AML12) cells and mouse primary hepatocytes were incubated with oleic acid or sodium palmitate in vitro to explore the role of PLD1 in the development of hepatic steatosis. Hepatic PLD1 expression was evaluated in liver biopsy samples in patients with NAFLD.ResultsPLD1 expression levels were increased in the hepatocytes of patients with NAFLD and HFD-fed mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited decreased plasma glucose and lipid levels as well as lipid accumulation in liver tissues after HFD feeding. Transcriptomic analysis showed that hepatocyte-specific deficiency of PLD1 decreased Cd36 expression in steatosis liver tissues, which was confirmed at the protein and gene levels. In vitro, specific inhibition of PLD1 with VU0155069 or VU0359595 decreased CD36 expression and lipid accumulation in oleic acid- or sodium palmitate-treated AML12 cells or primary hepatocytes. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acid and lysophosphatidic acid levels in liver tissues with hepatic steatosis. Furthermore, phosphatidic acid, the downstream product of PLD1, increased the expression levels of CD36 in AML12 cells, which was reversed by a PPARγ antagonist.ConclusionsHepatocyte-specific Pld1 deficiency ameliorates lipid accumulation and NAFLD development by inhibiting the PPARγ/CD36 pathway. PLD1 may be a new target for the treatment of NAFLD.Impact and implicationsThe involvement of PLD1 in hepatocyte lipid metabolism and NAFLD has not been explicitly explored. In this study, we found that the inhibition of hepatocyte PLD1 exerted potent protective effects against HFD-induced NAFLD, which were attributable to a reduction in PPARγ/CD36 pathway-mediated lipid accumulation in hepatocytes. Targeting hepatocyte PLD1 may be a new target for the treatment of NAFLD.

Dataset Information

Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.

Publications

Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.

Similar Datasets

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