Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

Abstract

Objective: Chemokine-like receptor 1 (CMKLR1) ligands chemerin and resolvin E1 are suggested to have a role in non-alcoholic fatty liver disease (NAFLD). Here, expression of CMKLR1 in liver cells and NAFLD was studied. Methods: Primary human hepatocytes and liver of patients with and without liver steatosis were used. Human liver tissue was obtained according to the guidelines of the charitable state-controlled foundation Human Tissue & Cell Research (HTCR) with the patient's informed consent. To induce NASH mice were fed a methionine-choline deficient diet for 6 weeks. Results: CMKLR1 was detected in primary human hepatocytes (PHH), Kupffer cells, bile-duct cells and hepatic stellate cells. In human fatty liver and in fibrotic liver of mice fed a methionine-choline deficient diet CMKLR1 protein was reduced. Hepatocytes are the major cells in the liver and effects of adipokines, cytokines and lipids on CMKLR1 in PHH were analysed. Increased cellular triglyceride or cholesterol content, lipopolysaccharide, IL–6, TNF and leptin did not influence CMKLR1 levels in PHH whereas profibrotic TGFbeta tended to reduce CMKLR1. Adiponectin strongly upregulated CMKLR1 mRNA and protein, and CMKLR1 was suppressed in the liver of adiponectin deficient mice. Conclusion: These data indicate that low CMKLR1 in NAFLD may partly result from reduced adiponectin activity.