Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters

被引:6
作者
Guo, Jiabao [1 ]
Miao, Guolin [1 ]
Zhang, Wenxi [1 ]
Shi, Haozhe [1 ]
Lai, Pingping [1 ]
Xu, Yitong [1 ]
Zhang, Lianxin [1 ]
Chen, Gonglie [1 ]
Han, Yufei [1 ]
Zhao, Ying [3 ]
Liu, Geroge [1 ]
Zhang, Ling [1 ]
Wang, Yuhui [1 ]
Huang, Wei [1 ]
Xian, Xunde [1 ,2 ]
机构
[1] Peking Univ, Inst Cardiovasc Sci, Sch Basic Med Sci, State Key Lab Vasc Homeostasis & Remodeling, Beijing, Peoples R China
[2] Peking Univ Third Hosp, Beijing Key Lab Cardiovasc Receptors Res, Beijing, Peoples R China
[3] China Japan Friendship Hosp, Dept Urol, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
Apolipoprotein A5; Syrian golden hamster; hypertriglyceridemia; nonalcoholic fatty liver disease; REV-ERB-ALPHA; APOLIPOPROTEIN A5; HYPERTRIGLYCERIDEMIA; TRIGLYCERIDES; METABOLISM; IMPROVES; HUMANS; GENE; MICE; HDL;
D O I
10.7150/thno.91084
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs). Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated. Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features. Then, the ApoA5-deficient (ApoA5-/-) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD). Results: ApoA5-/- hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue. An HFD challenge predisposed ApoA5-/hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH). Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively. Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5-/- hamsters significantly ameliorated fatty liver without affecting plasma lipid levels. Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5-/hamsters. Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future.
引用
收藏
页码:2036 / 2057
页数:22
相关论文
共 39 条
[1]   Triglyceride Metabolism in the Liver [J].
Alves-Bezerra, Michele ;
Cohen, David E. .
COMPREHENSIVE PHYSIOLOGY, 2018, 8 (01) :1-22
[2]   Brown adipose tissue activity controls triglyceride clearance [J].
Bartelt, Alexander ;
Bruns, Oliver T. ;
Reimer, Rudolph ;
Hohenberg, Heinz ;
Ittrich, Harald ;
Peldschus, Kersten ;
Kaul, Michael G. ;
Tromsdorf, Ulrich I. ;
Weller, Horst ;
Waurisch, Christian ;
Eychmueller, Alexander ;
Gordts, Philip L. S. M. ;
Rinninger, Franz ;
Bruegelmann, Karoline ;
Freund, Barbara ;
Nielsen, Peter ;
Merkel, Martin ;
Heeren, Joerg .
NATURE MEDICINE, 2011, 17 (02) :200-U93
[3]   Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models [J].
Basu, Debapriya ;
Bornfeldt, Karin E. .
FRONTIERS IN ENDOCRINOLOGY, 2020, 11
[4]   Dietary factors and low-grade inflammation in relation to overweight and obesity [J].
Calder, Philip C. ;
Ahluwalia, Namanjeet ;
Brouns, Fred ;
Buetler, Timo ;
Clement, Karine ;
Cunningham, Karen ;
Esposito, Katherine ;
Jonsson, Lena S. ;
Kolb, Hubert ;
Lansink, Mirian ;
Marcos, Ascension ;
Margioris, Andrew ;
Matusheski, Nathan ;
Nordmann, Herve ;
O'Brien, John ;
Pugliese, Giuseppe ;
Rizkalla, Salwa ;
Schalkwijk, Casper ;
Tuomilehto, Jaakko ;
Waernberg, Julia ;
Watzl, Bernhard ;
Winklhofer-Roob, Brigitte M. .
BRITISH JOURNAL OF NUTRITION, 2011, 106 :S1-S78
[5]   ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content [J].
Camporez, Joao Paulo G. ;
Kanda, Shoichi ;
Petersen, Max C. ;
Jornayvaz, Francois R. ;
Samuel, Varman T. ;
Bhanot, Sanjay ;
Petersen, Kitt Falk ;
Jurczak, Michael J. ;
Shulman, Gerald I. .
JOURNAL OF LIPID RESEARCH, 2015, 56 (03) :526-536
[6]   Modulation of phenotypic expression of APOA5 Q97X and L242P mutations [J].
Charriere, S. ;
Cugnet, C. ;
Guitard, M. ;
Bernard, S. ;
Groisne, L. ;
Charcosset, M. ;
Pruneta-Deloche, V. ;
Merlin, M. ;
Billon, S. ;
Delay, M. ;
Sassolas, A. ;
Moulin, P. ;
Marcais, C. .
ATHEROSCLEROSIS, 2009, 207 (01) :150-156
[7]   Plasma apolipoprotein A5 and triglycerides in type 2 diabetes [J].
Dallinga-Thie, G. M. ;
Van Tol, A. ;
Hattori, H. ;
Zee, L. C. Van Vark-Van der ;
Jansen, H. ;
Sijbrands, E. J. G. .
DIABETOLOGIA, 2006, 49 (07) :1505-1511
[8]   Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk [J].
Das Pradhan, Aruna ;
Glynn, Robert J. ;
Fruchart, Jean-Charles ;
MacFadyen, Jean G. ;
Zaharris, Elaine S. ;
Everett, Brendan M. ;
Campbell, Stuart E. ;
Oshima, Ryu ;
Amarenco, Pierre ;
Blom, Dirk J. ;
Brinton, Eliot A. ;
Eckel, Robert H. ;
Elam, Marshall B. ;
Felicio, Joao S. ;
Ginsberg, Henry N. ;
Goudev, Assen ;
Ishibashi, Shun ;
Joseph, Jacob ;
Kodama, Tatsuhiko ;
Koenig, Wolfgang ;
Leiter, Lawrence A. ;
Lorenzatti, Alberto J. ;
Mankovsky, Boris ;
Marx, Nikolaus ;
Nordestgaard, Borge G. ;
Pall, Denes ;
Ray, Kausik K. ;
Santos, Raul D. ;
Soran, Handrean ;
Susekov, Andrey ;
Tendera, Michal ;
Yokote, Koutaro ;
Paynter, Nina P. ;
Buring, Julie E. ;
Libby, Peter ;
Ridker, Paul M. .
NEW ENGLAND JOURNAL OF MEDICINE, 2022, 387 (21) :1923-1934
[9]   Dysregulated lipid metabolism links NAFLD to cardiovascular disease [J].
Deprince, Audrey ;
Haas, Joel T. ;
Staels, Bart .
MOLECULAR METABOLISM, 2020, 42
[10]   Increased apolipoprotein A5 expression in human and rat non-alcoholic fatty livers [J].
Feng, Qin ;
Baker, Susan S. ;
Liu, Wensheng ;
Arbizu, Ricardo A. ;
Aljomah, Ghanim ;
Khatib, Maan ;
Nugent, Colleen A. ;
Baker, Robert D. ;
Forte, Trudy M. ;
Hu, Yiyang ;
Zhu, Lixin .
PATHOLOGY, 2015, 47 (04) :341-348