C/EBP‐beta Regulates Lipid Homeostasis and Autophagy Activation in Liver and Macrophages

Abstract

Hyperlipidemia and macrophage foam cell formation result from dysregulation of lipid metabolism and are associated with obesity and atherosclerosis. Autophagy is a lysosomal degradative pathway that plays a crucial role in the metabolism and storage of cellular lipids. However, the molecular connection between autophagy and lipid homeostasis remains elusive. CCAAT/enhancer binding protein‐beta(C/EBPb) is a transcription factor and an important regulator of hepatic steatosis, inflammation, and ER stress. However, whether C/EBPb plays a role in lipid balance in liver and macrophage foam cells via interacting with autophagy machinery remains unexplored. The present study demonstrated that hematopoietic C/EBPb deletion in ApoE‐/‐(C/EBPb‐/‐→ApoE‐/‐) mice attenuated high fat/high cholesterol(HF/HC) diet (11 wks.) mediated induction of hepatic and serum cholesterol levels and genes implicated in TG (fatty acid synthase, stearoyl‐CoA desaturase) and cholesterol metabolism (HMG‐CoA reductase) compared to control (WT→ApoE‐/‐) mice. In addition, increased expression of autophagy protein (ATG5) and reduction of inflammasome activation were found in liver of (C/EBPb‐/‐→ApoE‐/‐) mice. Interestingly, silencing of C/EBPb in RAW 264.7 macrophage cells prevented atherogenic lipid mediated foam cell formation and cholesterol accumulation but increased autophagy activation, and cholesterol efflux. The present results suggest that C/EBPb may interact with autophagy machinery to regulate lipid metabolism in liver and macrophage foam cells. Funded by AHA Beginning Grant In Aid and Startup Fund (Texas Tech University).