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

Abstract

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.

Changes in circulating miRNA19a-3p precede insulin resistance programmed by intra-uterine growth retardation in mice

“…The alpha, beta, delta, and gamma 1,3-PPAR genes are expressed in the liver and encode proteins acting as lipid sensors in metabolism [ 65 , 66 ]. PPAR gamma has also been implicated in the M1 to M2 transition of macrophages in response to fatty acids [ 67 ], thereby affecting hepatocyte metabolism by modulating local inflammatory processes. Moreover, the potential regulation of PPAR gamma expression at the DNA levels (through methylation) and the direct role of this regulation in the placenta in fetal growth restriction both suggest a crucial role in the regulation of metabolism after IUGR [ 68 , 69 ].…”

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…In animal models, rosiglitazone protects against HFD-induced hepatic steatosis and reduces hepatic lipid content by increasing the expression of genes involved in beta-oxidation and decreasing the expression of lipogenic genes. These beneficial effects of rosiglitazone on lipid metabolism are accompanied by a decrease in hepatic M1 macrophages and modulation of the TLR4/NF-κB signaling pathways [368]. In the MCD model, rosiglitazone improves hepatic steatosis, inflammation, and fibrosis and reduces the expression of the HSC activator TGF-β [369].…”

Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy

“…Indeed, we have previously shown that extracellular vesicles released from steatotic hepatocytes induce an inflammatory response in Kupffer cells and a fibrogenic response in hepatic stellate cells [43]. Direct effects of free fatty acids on Kupffer cells include M1 polarization leading to a pro-inflammatory phenotype [44,45]. Lipotoxicity, defined as a harmful effect of lipid accumulation in non-adipose tissue, is considered a central mechanism in NAFLD progression [46].…”