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Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107.

ABSTRACT: Activation of hepatic stellate cells (HSCs) is a key inducer of liver fibrogenesis in nonalcoholic fatty liver disease (NAFLD). Exosomes play an important role between hepatocytes and HSCs. This study aims to explore the role of exosomes derived from palmitic acid (PA)-treated hepatocytes in regulating HSCs (LX-2 cell) proliferation and activation and the underlying mechanisms. Exosomes were isolated from PA-treated human normal hepatocytes and incubated with LX-2 cells. Cell Counting Kit-8 (CCK-8) was performed to determine LX-2 cell proliferation, and the expression of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1) were examined to evaluateLX-2 cell activation. PA induced hepatocytes to release more exosomes enriched in miR-107. Mechanically, on the one hand, exosomes from PA-treated hepatocytes shuttled miR-107 to LX-2 cells, where miR-107 activated Wnt signaling by targeting DKK1 and thereby induced LX-2 cell activation; on the other hand, PA-treated hepatocytes derived exosomes also delivered miR-107 to CD4 + T lymphocytes, where miR-107 elevated IL-9 expression by targeting Foxp1, which bound to the IL-9 promoter in CD4 + T cells and suppressed Th9 cell differentiation and reduced IL-9 expression, and thus promoted LX-2 cell activation by activating Raf/MEK/ERK signaling pathway.

SUBMITTER: Wang W

PROVIDER: S-EPMC8263701 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimFree fatty acid-induced lipotoxicity plays a crucial role in the progression of nonalcoholic fatty liver disease (NAFLD). In the present study we investigated the effects of a high-fat diet and free fatty acids on the autophagic process in hepatocytes in vivo and in vitro and the underlying mechanisms.MethodsLC3-II expression, a hallmark of autophagic flux, was detected in liver specimens from patients with non-alcoholic steatohepatitis (NASH) as well as in the livers of C57BL/6 mice fed a high-fat diet (HFD) up to 16 weeks. LC3-II expression was also analyzed in human SMMC-7721 and HepG2 hepatoma cells exposed to palmitic acid (PA), a saturated fatty acid. PA-induced apoptosis was detected by Annexin V staining and specific cleavage of PARP in the presence and absence of different agents.ResultsLC3-II expression was markedly increased in human NASH and in liver tissues of HFD-fed mice. Treatment of SMMC-7721 cells with PA increased LC3-II expression in time- and dose-dependent manners, whereas the unsaturated fatty acid oleic acid had no effect. Inhibition of autophagy with 3MA sensitized SMMC-7721 cells to PA-induced apoptosis, whereas activation of autophagy by rapamycin attenuated PA-induced PARP cleavage. The autophagy-associated proteins Beclin1 and Atg5 were essential for PA-induced autophagy in SMMC-7721 cells. Moreover, pretreatment with SP600125, an inhibitor of JNK, effectively abrogated PA-mediated autophagy and apoptosis. Specific knockdown of JNK2, but not JNK1, in SMMC-7721 cells significantly suppressed PA-induced autophagy and enhanced its pro-apoptotic activity; whereas specific knockdown of JNK1 had the converse effect. Similar results were obtained when HepG2 cells were tested.ConclusionJNK1 promotes PA-induced lipoapoptosis, whereas JNK2 activates pro-survival autophagy and inhibits PA lipotoxicity. Our results suggest that modulation of autophagy may have therapeutic benefits in the treatment of lipid-related metabolic diseases.

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Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107.

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