2. Academic Validation
  3. SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis

SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis

  • Metabolism. 2023 Jul 6;155657. doi: 10.1016/j.metabol.2023.155657.
Yunfeng Shen 1,  Lidan Cheng 2,  Minxuan Xu 3,  Wei Wang 4,  Zhiping Wan 5,  Haixia Xiong 1,  Wanrong Guo 6,  Mengyin Cai 7,  Fen Xu 8
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang 330006, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China.
  • 2 Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Endocrinology and Metabolism, Jiujiang University Affiliated Hospital, Jiujiang 330300, China.
  • 3 Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
  • 4 Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Gastroenterology, the First Affiliated Hospital of Yangtze University, Jingzhou 434000, China.
  • 5 Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
  • 6 Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
  • 7 Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China. Electronic address: [email protected].
  • 8 Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China. Electronic address: [email protected].
PMID: 37422021 DOI: 10.1016/j.metabol.2023.155657
Abstract

Background and rationale: Activation of hepatic stellate cells (HSCs), the central event of fibrosis, indicates the severe stage of non-alcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) participate in this process. Treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) alleviates liver fibrosis in patients with type 2 diabetes and NAFLD; however, the role of SGLT2i in ameliorating liver fibrosis in NAFLD by regulating miRNAs remains unclear.

Approach and results: We monitored the expression of NAFLD-associated miRNAs in the livers of two NAFLD models and observed high expression of miR-34a-5p. miR-34a-5p was highly expressed in mouse primary liver non-parenchymal cells and LX-2 HSCs, and this miRNA was positively correlated with alanine transaminase levels in NAFLD models. Overexpression of miR-34a-5p enhanced LX-2 activation, whereas its inhibition prevented HSCs activation by regulating the TGFβ signaling pathway. The SGLT2i empagliflozin significantly downregulated miR-34a-5p, inhibited the TGFβ signaling pathway, and ameliorated hepatic fibrosis in NAFLD models. Subsequently, GREM2 was identified as a direct target of miR-34a-5p through database prediction and a dual-luciferase reporter assay. In LX-2 HSCs, the miR-34a-5p mimic and inhibitor directly downregulated and upregulated GREM2, respectively. Overexpressing GREM2 inactivated the TGFβ pathway whereas GREM2 knockdown activated it. Additionally, empagliflozin upregulated Grem2 expression in NAFLD models. In methionine- and choline-deficient diet-fed ob/ob mice, a fibrosis model, empagliflozin downregulated miR-34a-5p and upregulated Grem2 to improve liver fibrosis.

Conclusions: Empagliflozin ameliorates NAFLD-associated fibrosis by downregulating miR-34a-5p and targeting GREM2 to inhibit the TGFβ pathway in HSCs.

Keywords

Fibrosis; GREM2; Non-alcoholic fatty liver disease; Sodium-glucose cotransporter 2 inhibitor; miR-34a-5p.

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