Bidirectional Regulation of Sodium Acetate on Macrophage Activity and Its Role in Lipid Metabolism of Hepatocytes

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5536
• Main Authors: Li, Weiwei, Deng, Mingjuan, Gong, Jiahui, Hou, Yichao, Zhao, Liang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Accumulation; Acetates; Acetic acid; AMP-Activated Protein Kinases - metabolism; AMPK; Bone marrow; c-Jun protein; Cholesterol; dose-dependent effects; Fatty acids; Fatty liver; Gene expression; hepatocyte; Hepatocytes; Hepatocytes - metabolism; Humans; Inflammation; Interleukin 1; Interleukin 6; Interleukins; Intestinal microflora; Intracellular; Kinases; Kupffer cells; lipid accumulation; Lipid Metabolism; Lipids; Lipids - pharmacology; Lipopolysaccharides - pharmacology; Liver; Liver diseases; Low concentrations; Macrophages; Macrophages - metabolism; Metabolism; Metabolites; Microbiota; Microbiota (Symbiotic organisms); Mitochondrial uncoupling protein 2; NF-kappa B - metabolism; NF-κB protein; Nitric-oxide synthase; Non-alcoholic Fatty Liver Disease - metabolism; Phosphorylation; Physiological aspects; Signal transduction; Sodium acetate; Sodium Acetate - pharmacology; Transcription factors; Triglycerides; Tumor necrosis factor-α; China; California; dose-dependent effects; AMPK; macrophages; hepatocyte; sodium acetate; lipid accumulation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065536

Short-chain fatty acids (SCFAs) are important metabolites of the intestinal flora that are closely related to the development of non-alcoholic fatty liver disease (NAFLD). Moreover, studies have shown that macrophages have an important role in the progression of NAFLD and that a dose effect of sodium acetate (NaA) on the regulation of macrophage activity alleviates NAFLD; however, the exact mechanism of action remains unclear. This study aimed to assess the effect and mechanism of NaA on regulating the activity of macrophages. RAW264.7 and Kupffer cells cell lines were treated with LPS and different concentrations of NaA (0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, and 5 mM). Low doses of NaA (0.1 mM, NaA-L) significantly increased the expression of inflammatory factors tumor necrosis factor-α ( ), interleukin-6 ( ), and interleukin 1 beta ( ); it also increased the phosphorylation of inflammatory proteins nuclear factor-κB p65 (NF-κB p65) and c-Jun ( ), and the M1 polarization ratio of RAW264.7 or Kupffer cells. Contrary, a high concentration of NaA (2 mM, NaA-H) reduced the inflammatory responses of macrophages. Mechanistically, high doses of NaA increased intracellular acetate concentration in macrophages, while a low dose had the opposite effect, consisting of the trend of changes in regulated macrophage activity. Besides, and/or were not involved in the regulation of macrophage activity by NaA. NaA significantly increased total intracellular cholesterol (TC), triglycerides (TG), and lipid synthesis gene expression levels in macrophages and hepatocytes at either high or low concentrations. Furthermore, NaA regulated the intracellular AMP/ATP ratio and AMPK activity, achieving a bidirectional regulation of macrophage activity, in which the PPARγ/UCP2/AMPK/iNOS/IκBα/NF-κB signaling pathway has an important role. In addition, NaA can regulate lipid accumulation in hepatocytes by NaA-driven macrophage factors through the above-mentioned mechanism. The results revealed that the mode of NaA bi-directionally regulating the macrophages further affects hepatocyte lipid accumulation.