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

Abstract

Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated that MCPIP1 regulates lipid metabolism both in adipose tissue and in hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of nonalcoholic fatty liver disease (NAFLD). We used control Mcpip1^fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1^fl/fl LysM^Cre ) and in hepatocytes (Mcpip1^fl/fl Alb^Cre ), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1^fl/fl LysM^Cre mice fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in low plasma glucose level and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma and high Tnfa, Il6, IL1b mRNA levels in the liver and brown adipose tissue (BAT). Proinflammatory leukocyte infiltration into BAT, together with low expression of Ucp1 and Ppargc1a, resulted in hypothermia of 22-week-old Mcpip1^fl/fl LysM^Cre mice. On the other hand, there were no significant changes in phenotype in Mcpip1^fl/fl Alb^Cre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and β-oxidation in these mice, they remained asymptomatic. Upon feeding with a HFD, Mcpip1^fl/fl LysM^Cre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by low plasma glucose level and dyslipidemia, along with proinflammatory phenotype. Mcpip1^fl/fl Alb^Cre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1^fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected. We have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. 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.

Keywords: MCPIP1; NAFLD; fatty liver; inflammation; obesity.