Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts.

Background&AimsMonocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NF{kappa}B activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of non-alcoholic fatty liver disease (NAFLD). MethodsWe used mice with deletion of Mcpip1 in myeloid leukocytes (Mcpip1LysMKO) and in hepatocytes (Mcpip1AlbKO), which were fed chow or a high-fat diet (HFD) for 12 weeks. ResultsMcpip1LysMKO mice which were fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which was followed by hypoglycemia and dyslipidemia. These animals also developed systemic inflammation, manifested by increased concentrations of cytokines in the plasma. On the other hand, there were no significant changes in phenotype in Mcpip1AlbKO mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and {beta}-oxidation in these mice, they remained asymptomatic. Upon feeding them a HFD, Mcpip1LysMKO mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by hypoglycemia and dyslipidemia, along with proinflammatory phenotype with symptoms of cachexia. Mcpip1AlbKO animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and had no changes in the level of soluble factors tested in the plasma. ConclusionsIn conclusion, we have demonstrated that Mcpip1 protein plays an important role in the development of fatty liver disease, hepatitis, and during NAFLD progression. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.