이용호 (연세대학교 의과대학)

한빛사논문

조회497

연세대학교 의과대학

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Metab.-Clin. Exp., 2023 Jun 3;145:155612 | https://doi.org/10.1016/j.metabol.2023.155612 Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis

Hye Jin Chun^a,b,1, Eun Ran Kim ^b,c,1, Minyoung Lee ^b,d,1, Da Hyun Choi ^a,b, Soo Hyun Kim ^b, Eugene Shin ^b, Jin-Hong Kim ^e, Jin Won Cho ^a,f, Dai Hoon Han ^g, Bong-Soo Cha ^b,d, Yong-ho Lee ^a,b,d

^aInterdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, Republic of Korea
^bDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
^cDivision of Endocrine and Kidney Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, Chungbuk 28159, Republic of Korea
^dInstitute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
^eDepartment of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
^fDepartment of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul 03722, Republic of Korea.
^gDepartment of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

¹Co-first authors.
Correspondence to: D. H. Han, Bong-Soo Cha, Yong-ho Lee

Abstract

Aims: Steatosis reducing effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-alcoholic steatohepatitis (NASH) has been consistently reported in humans, but their mechanism remains uncertain. In this study, we examined the expression of SGLT2 in human livers and investigated the crosstalk between SGLT2 inhibition and hepatic glucose uptake, intracellular O-GlcNAcylation, and autophagic regulation in NASH.

Materials and methods: Human liver samples obtained from subjects with/without NASH were analyzed. For in vitro studies, human normal hepatocytes and hepatoma cells were treated with SGLT2 inhibitor under high-glucose and high-lipid conditions. NASH in vivo was induced by a high-fat, -fructose, and -cholesterol Amylin liver NASH (AMLN) diet for 10 weeks followed by an additional 10 weeks with/without SGLT2 inhibitor (empagliflozin 10 mg/kg/day).

Results: Liver samples from subjects with NASH were associated with increased SGLT2 and O-GlcNAcylation expression compared with controls. Under NASH condition (in vitro condition with high glucose and lipid), intracellular O-GlcNAcylation and inflammatory markers were increased in hepatocytes and SGLT2 expression was upregulated; SGLT2 inhibitor treatment blocked these changes by directly reducing hepatocellular glucose uptake. In addition, decreased intracellular O-GlcNAcylation by SGLT2 inhibitor promoted autophagic flux through AMPK-TFEB activation. In the AMLN diet-induced NASH mice model, SGLT2 inhibitor alleviated lipid accumulation, inflammation, and fibrosis through autophagy activation related to decreased SGLT2 expression and O-GlcNAcylation in the liver.

Conclusions: This study firstly demonstrates increased SGLT2 expression in NASH and secondly reveals the novel effect of SGLT2 inhibition on NASH through autophagy activation mediated by inhibition of hepatocellular glucose uptake and consequently decreased intracellular O-GlcNAcylation.

논문정보

형식Research article
게재일2023년 06월 (BRIC 등록일 2023-06-20)
연구진국내 연구진
분야 의약학 > 응용의학

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