Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced Steatosis

被引：18

作者：

Dong, Zeyu ^{[1
]}

He, Fangzhou ^{[1
]}

Yan, Xiaosong ^{[1
]}

Xing, Yuanming ^{[1
,2
]}

Lei, Yuyang ^{[1
,2
]}

Gao, Jie ^{[1
,5
]}

He, Ming ^{[3
]}

Li, Dongmin ^{[4
]}

Bai, Liang ^{[1
,2
,5
]}

Yuan, Zuyi ^{[2
]}

Shyy, John Y-J ^{[1
,3
]}

机构：

[1] Xi An Jiao Tong Univ, Inst Cardiovasc Sci, Translat Med Inst, Hlth Sci Ctr, Xian, Shaanxi, Peoples R China

[2] Xi An Jiao Tong Univ, Dept Cardiol, Affiliated Hosp 1, Xian, Shaanxi, Peoples R China

[3] Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA USA

[4] Xi An Jiao Tong Univ, Dept Genet & Mol Biol, Hlth Sci Ctr, Xian, Shaanxi, Peoples R China

[5] Xi An Jiao Tong Univ, Sch Basic Med Sci, Dept Lab Anim Sci, Xian, Shaanxi, Peoples R China

来源：

CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY | 2022年 / 13卷 / 04期

基金：

中国博士后科学基金; 国家重点研发计划; 中国国家自然科学基金;

关键词：

25-HC; Bile Acid Metabolism; Ch25h; CYP7A1; Hepatic Steatosis; FARNESOID-X-RECEPTOR; FATTY LIVER; BILE-ACIDS; DIFFERENTIAL REGULATION; HUMAN CYP7A1; OBESE MICE; EXPRESSION; GENE; LXR; METABOLISM;

D O I：

10.1016/j.jcmgh.2021.12.018

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Cholesterol 25-hydroxylase (Ch25h), converting cholesterol to 25-hydroxycholesterol (25-HC), is critical in modulating cellular lipid metabolism and anti-inflammatory and antiviral activities. However, its role in nonalcoholic fatty liver disease remains unclear.& nbsp;METHODS: Ch25h expression was detected in livers of ob/ob mice and E3 rats fed a high-fat diet (HFD). Gain-or loss-of-function of Ch25h was performed using Ch25h(+/+) (wild type [WT]) mice receiving AAV8-Ch25h or Ch25h knockout (Ch25h(-/-)) mice. WT mice fed an HFD were administered with 25-HC. The Ch25h-LXRa-CYP axis was measured in primary hepatocytes isolated from WT and Ch25h(-/-) mice.& nbsp;RESULTS: We found that Ch25h level was decreased in livers of ob/ob mice and E3 rats fed an HFD. Ch25h(-/- )mice fed an HFD showed aggravated fatty liver and decreased level of cytochrome P450 7A1 (CYP7A1), in comparison with their WT littermates. RNA-seq analysis revealed that the differentially expressed genes in livers of HFD-fed Ch25h(-/- )mice were involved in pathways of positive regulation of lipid metabolic process, steroid metabolic process, cholesterol metabolic process, and bile acid biosynthetic process. As gain-of-function experiments, WT mice receiving AAV8-Ch25h or 25-HC showed alleviated NAFLD, when compared with the control group receiving AAV8-control or vehicle control. Consistently, Ch25h overexpression significantly elevated the levels of primary and secondary bile acids and CYP7A1 but decreased those of small heterodimer partner and FGFR4.& nbsp;CONCLUSIONS: Elevated levels of Ch25h and its enzymatic product 25-HC alleviate HFD-induced hepatic steatosis via regulating enterohepatic circulation of bile acids. The underlying mechanism involves 25-HC activation of CYP7A1 via liver X receptor. These data suggest that targeting Ch25h or 25-HC may have therapeutic advantages against nonalcoholic fatty liver disease.

引用

页码：1161 / 1179

页数：19

共 42 条

[1] Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs[J]. Adams, CM;Reitz, J;De Brabander, JK;Feramisco, JD;Li, L;Brown, MS;Goldstein, JL. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004(50)
[2] Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design[J]. Anstee, Quentin M.;Neuschwander-Tetri, Brent A.;Wong, Vincent Wai-Sun;Abdelmalek, Manal F.;Younossi, Zobair M.;Yuan, Jiacheng;Pecoraro, Maria Lucia;Seyedkazemi, Star;Fischer, Laurent;Bedossa, Pierre;Goodman, Zachary;Alkhouri, Naim;Tacke, Frank;Sanyal, Arun. CONTEMPORARY CLINICAL TRIALS, 2020
[3] Transcription Coactivator Mediator Subunit MED1 Is Required for the Development of Fatty Liver in the Mouse[J]. Bai, Liang;Jia, Yuzhi;Viswakarma, Navin;Huang, Jiansheng;Vluggens, Aurore;Wolins, Nathan E.;Jafari, Nadereh;Rao, M. Sambasiva;Borensztajn, Jayme;Yang, Gongshe;Reddy, Janardan K. HEPATOLOGY, 2011(04)
[4] Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet[J]. Chen, JY;Levy-Wilson, B;Goodart, S;Cooper, AD. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002(45)
[5] Chiang John Y L, 2017, Liver Res, V1, P3, DOI 10.1016/j.livres.2017.05.001
[6] The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Chow, Monica D.;Lee, Yi-Horng;Guo, Grace L. MOLECULAR ASPECTS OF MEDICINE, 2017
[7] 25-Hydroxycholesterols in innate and adaptive immunity[J]. Cyster, Jason G.;Dang, Eric V.;Reboldi, Andrea;Yi, Tangsheng. NATURE REVIEWS IMMUNOLOGY, 2014(11)
[8] Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders[J]. Ferrell, Jessica M.;Boehme, Shannon;Li, Feng;Chiang, John Y. L. JOURNAL OF LIPID RESEARCH, 2016(07)
[9] PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation[J]. Gao, Qian;Jia, Yuzhi;Yang, Gongshe;Zhang, Xiaohong;Boddu, Prajwal C.;Petersen, Bryon;Narsingam, Saiprasad;Zhu, Yi-Jun;Thimmapaya, Bayar;Kanwar, Yashpal S.;Reddy, Janardan K. AMERICAN JOURNAL OF PATHOLOGY, 2015(05)
[10] Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC)[J]. Gilat, T;Leikin-Frenkel, A;Goldiner, I;Juhel, C;Lafont, H;Gobbi, D;Konikoff, FM. HEPATOLOGY, 2003(02)

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