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Metab.-Clin. Exp., Apr 12 2025, S0026-0495(25)00135-0 | https://doi.org/10.1016/j.metabol.2025.156266 Hepatic miR-93 promotes the pathogenesis of metabolic dysfunction-associated steatotic liver disease by suppressing SIRT1

Yo Han Lee ^a,1, Jinyoung Lee ^b,1, Joonho Jeong ^c,1, Kieun Park ^a,1, Bukyung Baik^a, Yuseong Kwon ^b, Kimyeong Kim ^a, Keon Woo Khim ^a, Haneal Ji ^a, Ji Young Lee^a, Kwangho Kim^a, Ji Won Kim^a, Tam Dao ^d,e, Misung Kim ^f, Tae Young Lee ^g, Yong Ryoul Yang ^h, Haejin Yoon ^a, Dongryeol Ryu ^d,e, Seonghwan Hwang ^b, Haeseung Lee ^b, Dougu Nam ^a, Won Kon Kim ⁱ, Neung Hwa Park ^c, Hwayoung Yun ^b, Jang Hyun Choi ^a

^aDepartment of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
^bCollege of Pharmacy and Research Institute for Drug Development, Pusan National University (PNU), Busan 46241, Republic of Korea
^cDivision of Hepatology, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital (UUH), Ulsan 44033, Republic of Korea
^dDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
^eDepartment of Molecular Cell Biology, Sungkyunkwan University School of Medicine (SKKU), Suwon 16419, Republic of Korea
^fDepartment of Pathology, University of Ulsan College of Medicine, Ulsan University Hospital (UUH), Ulsan 44033, Republic of Korea
^gDepartment of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital (UUH), Ulsan 44033, Republic of Korea
^hAging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
ⁱMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea

¹These authors contributed equally to this work.
Corresponding authors: Neung Hwa Park, Hwayoung Yun, Jang Hyun Choi

Abstract

Background and aims: The molecular mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain largely unclear; however, emerging evidence suggests that microRNAs (miRNAs) play a critical role in modulating transcriptional regulation of target genes involved in MASLD. This study aims to elucidate the role of miR-93 in lipid metabolism and MASLD progression.

Methods: We comprehensively analyzed miRNA expression profiles in liver tissues from patients with MASLD and diet-induced obese mice. miR-93 knockout (KO) mice were fed a high-fat-high-fructose (HFHFr) diet to assess the impact of miR-93 deficiency on MASLD. Transcriptome analysis was performed to elucidate the molecular mechanisms and role of miR-93 in MASLD. Additionally, we employed a high-throughput screening system to identify drugs capable of modulating miR-93 expression.

Results: miR-93 was significantly upregulated in the livers of patients with MASLD and diet-induced obese mice. miR-93 KO mice exhibited reduced hepatic steatosis. Specifically, miR-93 deficiency upregulated genes involved in fatty acid oxidation and downregulated genes associated with cholesterol biosynthesis. Sirtuin 1 (SIRT1) was identified as a direct target of miR-93, and miR-93 KO enhanced SIRT1 expression and activated the LKB1-AMPK signaling pathway. Niacin treatment downregulated miR-93, ameliorating hepatic steatosis by enhancing SIRT1 activity.

Conclusions: These findings implicate miR-93 as a novel therapeutic target for MASLD. The study demonstrates the therapeutic potential of niacin in modulating the miR-93/SIRT1 axis, providing a new potential treatment for MASLD, a disease with limited current treatment options.

논문정보

형식Research article
게재일2025년 04월 (BRIC 등록일 2025-04-15)
연구진국내 연구진
분야 생명과학 > 세포생물학

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