Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a Toll-like receptor 4/NF-κB signaling pathway.

Background And Aim: Chronic inflammation links closely to insulin resistance and lipid metabolism in nonalcoholic fatty liver disease (NAFLD). Macrophage M1 activation plays an important role in the initiation and continuing of pro-inflammatory response of NAFLD. Our study was to investigate whether macrophage M1/M2 polarization switching would affect hepatic inflammation and lipid metabolism through modulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity in vivo and in vitro.

Methods: RAW264.7 macrophages were treated with different fatty acids, and cell culture supernatants were collected to prepare conditioned media (CM). Different co-culture systems between primary hepatocytes and CM from macrophages were established. A PPAR-γ agonist or antagonist was administered to regulate PPAR-γ activity and macrophage polarization. M1/M2 phenotype markers, inflammatory signaling pathway, and lipid-related genes expression were determined. Wild-type C57BL/6 mice were fed a high-fat diet to induce NAFLD and given rosiglitazone to regulate PPAR-γ activity in vivo.

Results: Saturated fatty acids induced M1-polarized macrophages while polyunsaturated fatty acids induced M2-polarized macrophages. M1-polarized macrophages significantly promoted lipid synthesis and accumulation in primary hepatocytes through upregulation of a toll-like receptor 4 (TLR4)/NF-κB signaling pathway. The PPAR-γ agonist made lipid-induced M1-polarized macrophages switch to an M2-predominant phenotype, while PPAR-γ antagonist had the opposite effect. Macrophage polarization shifting subsequently affected lipid metabolism in primary hepatocytes. Administration of rosiglitazone improved high-fat diet induced hepatic steatosis and lipid metabolism through reducing hepatic TLR4/NF-κB expression and M1-polarized Kupffer cells.

Conclusions: Lipid-induced macrophage M1 polarization promoted hepatic lipid metabolism. Modulation of PPAR-γ activity could shift macrophage polarization and subsequently affect lipid metabolism. Upregulation of the TLR4/NF-κB signaling pathway is closely linked to dysregulated lipid metabolism in NAFLD.