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Downregulation of microRNA-300-3p promotes steatosis-to-MASH progression by regulating STX17

ABSTRACT: Background & aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) ranges from simple steatosis (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH). With the complex etiological factors associated with MAFLD, the molecular mechanism underlying the progression from steatosis to MASH has not been fully elucidated, resulting in a limited number of effective therapeutic interventions. Methods: We examined the profiling changes of MicroRNAs (miRNAs) in vivo and in vitro experiments and miR - 300 - 3p was identified as a crucial checkpoint in this process in the current experiments. The present studies were carried out to explore the role of miR - 300 - 3p in the advancement of MASH. Bioinformatic analysis, RNA - Sequencing, and dual - luciferase reporter assays were used to investigate the might target of miR - 300 - 3p. Results: We investigated the profiling changes of miRNA and identified miR - 300 - 3p is low expressed in mouse experiments and HepG2 cells. In vitro loss of function study revealed that suppression of miR - 300 - 3p in steatotic HepG2 cells could induce obvious inhibit cell autophagy, promote cell apoptosis, cause lipid accumulation, hepatic inflammation and injury, which are the primary characteristics within the pathology of MASH. STX17 was a predicted target gene of miR-300-3p through RNA-Sequencing, bioinformatic analysis and dual-luciferase reporter assays. Downregulation miR-300-3p was able to downregulate STX17 to promotes steatosis-to-MASH progression. In contrast, transduction of miR - 300 - 3p and over-STX17 inhibit steatosis-to_x0002_MASH progressionin. The results was inconsistent with canonical miRNA biology predicts, which indicated that the regulation of miR - 300 - 3p on STX17 might has context-dependent and involve indirect mechanism, feedback loop or multi-level control. Potentially clinically significant, the miR - 300 - 3p/STX17 regulatory axis has also been confirmed in human plasma. Expression level of miR - 300 - 3p and STX17 was reduced in plasma of MAFLD patients. Their expression levels were closely related to liver biochemical indicators and lipid profile indicators. Conclusion: Our research results highlight the function of the miR - 300 - 3p/ STX17 regulatory axis in the progression from steatosis to MASH. This suggests that either the supplementation of miR - 300 - 3p or STX17 may provide a promising therapeutic strategy for treating MASH in hepatocytes. The underlying mechanism through which miR - 300 - 3p regulates STX17 requires further investigation.

ORGANISM(S): Mus musculus

PROVIDER: GSE328114 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:Adipose tissue dysfunction results in hepatic lipid overload, driving the progression of liver steatosis and non-alcoholic steatohepatitis. The involvement of adipose tissue-derived small extracellular vesicles (sEVs) in initiating and propagating nonalcoholic fatty liver disease (NAFLD) remains unexplored. Herein, we unveiled that transplanting adipose tissue from high-fat diet (HFD)-fed mice exacerbated insulin resistance and liver steatosis in lean mice, and Sirt3 expression was markedly reduced in adipose tissue from both NAFLD patients and murine NAFLD models. Interestingly, fat-specific Sirt3 overexpression (Sirt3AKI) mice enhanced insulin sensitivity and improved liver steatosis under HFD feeding. Furthermore, adipose tissue-derived sEVs were found to regulate hepatic lipid metabolism in Sirt3AKI mice. In vitro studies demonstrated that Sirt3 overexpressing adipocytes (Sirt3OE) released sEVs to ameliorate lipid accumulation in palmitic acid/oleic acid (P/O)-stimulated hepatocytes. Conversely, sEVs derived from NAFLD patients exacerbated hepatic lipid accumulation in HFD-fed Sirt3AKI mice. MicroRNA sequencing further identified a significant decrease in miR-30a-3p levels in sEVs derived from Sirt3OE adipocytes. Fat-specific miR-30a-3p overexpression worsened hepatic steatosis in HFD-fed Sirt3AKI mice. In contrast, engineered sEVs loaded with miR-30a-3p antagonist or miR-30a-3p inhibition robustly enhanced insulin sensitivity and mitigated hepatic accumulation in HFD-fed mice. Mechanistically, CHIP-qPCR and CHIP-sequencing analyses revealed that Sirt3 suppressed miR-30a-3p transcription through H3K56 acetylation. Dual-luciferase reporter assays validated Beclin1 as a bona fide target mRNA of miR-30a-3p. Taken together, these findings highlight the critical role of exosomal microRNAs in mediating adipocyte-hepatocyte crosstalk, provide novel insights into the mechanisms underlying lipotoxicity in hepatocytes, and suggest miR-30a-3p inhibitor could be a therapeutic agent for NAFLD.

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Downregulation of microRNA-300-3p promotes steatosis-to-MASH progression by regulating STX17

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