Effect of hepatocyte fatty degeneration induced by free fatty acid on macrophage polarization

Xiaoyun LI; Xixi NI; Jing HUA

doi:10.3969/j.issn.1001-5256.2021.02.027

Volume 37 Issue 2

Mar. 2021

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Effect of hepatocyte fatty degeneration induced by free fatty acid on macrophage polarization

DOI: 10.3969/j.issn.1001-5256.2021.02.027

Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China

Received Date: 2020-08-27
Accepted Date: 2020-10-21
Published Date: 2021-02-20

Abstract

Abstract

Objective To investigate the effect of hepatocyte fatty degeneration induced by free fatty acid on macrophage polarization and the possible mechanism. Methods Primary hepatocytes of C57BL/6 mice were isolated by in situ collagenase perfusion, and then the hepatocytes were divided into control (NC) group and mixed free fatty acid (FFA) treatment group. A conditioned medium (CM) was prepared for hepatocytes and was used for the intervention of RAW264.7 macrophages. Oil red O staining was used to observe lipid deposition in hepatocytes; real-time PCR was used to measure the mRNA expression of lipid metabolism genes and macrophage M1/M2 polarization markers; ELISA was used to measure the levels of cytokines in supernatant; Western blot was used to measure the expression of proteins involved in the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway in macrophages. The independent samples t-test was used for comparison between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the Tukey test was used for further comparison between two groups. Results Compared with the NC group, the FFA treatment group had the deposition of massive lipid droplets in hepatocytes and significant increases in triglyceride and total cholesterol (t=15.65 and 3.49, both P < 0.05). Besides, FFA significantly increased the mRNA expression of the lipid synthesis genes SREBP1C and FASN (t=2.89 and 2.82, both P < 0.05) and reduced the mRNA expression of the lipid decomposition genes ACOX1 and CPT1A (t=14.30 and 3.36, both P < 0.05) in hepatocytes. FFA also induced significant increases in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β, and tumor necrosis factor-α (TNF-α) in supernatant (all P < 0.05). Compared with the CM-NC group, the CM-FFA group had significant increases in the mRNA expression of the M1 phenotype markers iNOS2, TNF-α, and IL-6 (all P < 0.05) and a significant reduction in the mRNA expression of the M2 phenotype marker interleukin-10 (P < 0.05). Moreover, Western blot showed that CM-FFA significantly upregulated the protein expression of TLR4, p-NF-κBp65, and p-ⅠκBα in macrophages (t=2.88, 3.69, and 3.54, all P < 0.05). Conclusion FFA-induced hepatocyte fatty degeneration and inflammation can promote M1 macrophage polarization, thereby initiating and triggering the development and progression of nonalcoholic fatty liver disease.
- Non-alcoholic Fatty Liver Disease,
- Macrophages,
- Fatty Acids

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Effect of hepatocyte fatty degeneration induced by free fatty acid on macrophage polarization

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