조윤일 (가천융합의과학원 / 가천대학교 한국마우스표현형연구센터) | 한빛사논문 > 한빛사

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가천융합의과학원 / 가천대학교 한국마우스표현형연구센터

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Exp. Mol. Med., 13 February 2025 | https://doi.org/10.1038/s12276-025-01403-6 Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue

Shi-Young Park ^1,2,12, Yoonil Cho ^1,3,12, Sae-Mi Son ^1,3, Jang Ho Hur ¹, Yeongmin Kim ^3,4, Hyunhee Oh ^1,2, Hui-Young Lee ^1,5, Sungwon Jung ^6,7, Sanghee Park ^4,8, Il-Young Kim ^1,4,5, Se-Jin Lee ^9,10 and Cheol Soo Choi ^1,5,11

¹Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
²Gachon Biomedical Convergence Institute, Gachon University Gil Medical Center, Incheon, Republic of Korea.
³Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of
Korea.
⁴Integrative Metabolic Fluxomics Lab, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
⁵Division of Molecular Medicine, Department of Medicine, Gachon University College of Medicine, Incheon, Republic of Korea.
⁶Department of Genome Medicine and Science, Gachon University College of Medicine, Incheon, Republic of Korea.
⁷Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea.
⁸Department of Exercise Rehabilitation, Gachon University, Incheon, Republic of Korea.
⁹The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
¹⁰ Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
¹¹Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon,
Republic of Korea.
¹²These authors contributed equally: Shi-Young Park, Yoonil Cho.

^*Corresponding author: correspondence to Cheol Soo Choi

Abstract

Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-14)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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