Ketogenic diet time-dependently prevents NAFLD through upregulating the expression of antioxidant protein metallothionein-2

作者全名：You, Yuehua; Huang, Yi; Wang, Xiaoyang; Ni, Hongbin; Ma, Qin; Ran, Haiying; Cai, Jingshu; Lin, Xiaojing; Luo, Ting; Wu, Chaodong; Xiao, Xiaoqiu; Ma, Li

作者地址：[You, Yuehua; Ni, Hongbin; Cai, Jingshu; Lin, Xiaojing; Luo, Ting; Xiao, Xiaoqiu; Ma, Li] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrinol, Chongqing 400016, Peoples R China; [You, Yuehua; Ni, Hongbin; Ma, Qin; Cai, Jingshu; Lin, Xiaojing; Xiao, Xiaoqiu; Ma, Li] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Translat Med Major Metab Dis, Chongqing 400016, Peoples R China; [Huang, Yi; Wang, Xiaoyang; Ran, Haiying] Army Med Univ, Biomed Anal Ctr, Chongqing 400038, Peoples R China; [Huang, Yi; Wang, Xiaoyang; Ran, Haiying] Chongqing Key Lab Cyt, Chongqing 400038, Peoples R China; [Ma, Qin] Chongqing Med Univ, Sch Publ Hlth & Management, Dept Nutr & Food Hyg, Chongqing 400016, Peoples R China; [Wu, Chaodong] Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX USA; [Xiao, Xiaoqiu; Ma, Li] Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China

通信作者：Xiao, XQ; Ma, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China.

来源：CLINICAL NUTRITION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001240086200001

JCR分区：Q1

影响因子：6.6

年份：2024

卷号：43

期号：6

开始页：1475

结束页：1487

文献类型：Article

关键词：NAFLD; Ketogenic diet; MT2; Lipid accumulation; PPAR a

摘要：Background & aims: The past few decades have witnessed a rapid growth in the prevalence of nonalcoholic fatty liver disease (NAFLD). While the ketogenic diet (KD) is considered for managing NAFLD, the safety and efficacy of the KD on NAFLD has been a controversial topic. Here, we aimed to investigate the effect of KD of different durations on metabolic endpoints in mice with NAFLD and explore the underlying mechanisms. Methods: NAFLD mice were fed with KD for 1, 2, 4 and 6 weeks, respectively. The blood biochemical indexes (blood lipids, AST, ALT and etc.) and liver fat were measured. The LC-MS/MS based proteomic analysis was performed on liver tissues. Metallothionein-2 (MT2) was knocked down with adenoassociated virus (AAV) or small interfering RNA (siRNA) in NAFLD mice and AML-12 cells, respectively. H&E, BODIPY and ROS staining were performed to examine lipid deposition and oxidative stress. Furthermore, MT2 protein levels, nucleus/cytoplasm distribution and DNA binding activity of peroxisome proliferators-activated receptors a (PPARa) were evaluated. Results: KD feeding for 2 weeks showed the best improvement on NAFLD phenotype. Proteomic analysis revealed that MT2 was a key candidate for different metabolic endpoints of NAFLD affected by different durations of KD feeding. MT2 knockdown in NAFLD mice blocked the effects of 2 weeks of KD feeding on HFD-induced steatosis. In mouse primary hepatocytes and AML-12 cells, MT2 protein levels were induced by b-hydroxybutyric acid (b-OHB). MT2 Knockdown blunted the effects of b-OHB on alleviating PA-induced lipid deposition. Mechanistically, 2 weeks of KD or b-OHB treatment reduced oxidative stress and upregulated the protein levels of MT2 in nucleus, which subsequently increased its DNA binding activity and PPARa protein expression. Conclusions: Collectively, these findings indicated that KD feeding prevented NAFLD in a time dependent manner and MT2 is a potential target contributing to KD improvement on steatosis. (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

基金机构：National Natural Science Foundation of China [31700725, 82071734, 81871222]; Natural Science Foundation of Chongqing, China [2020jcyj- msxmX0504]; Postgraduate Research and Innovation Project of Chongqing, China [CYB21167]

基金资助正文：This work was supported by the National Natural Science Foundation of China (31700725 to LM, 82071734 and 81871222 to XX) , the Natural Science Foundation of Chongqing, China (2020jcyj- msxmX0504 to LM) and the Postgraduate Research and Innovation Project of Chongqing, China (CYB21167 to YY) .