Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity

被引：106

作者：

Regnier, Marion ^{[1
]}

Polizzi, Arnaud ^{[1
]}

Smati, Sarra ^{[1
,2
]}

Lukowicz, Celine ^{[1
]}

Fougerat, Anne ^{[1
]}

Lippi, Yannick ^{[1
]}

Fouche, Edwin ^{[1
]}

Lasserre, Frederic ^{[1
]}

Naylies, Claire ^{[1
]}

Betoulieres, Colette ^{[1
]}

Barquissau, Valentin ^{[2
]}

Mouisel, Etienne ^{[2
]}

Bertrand-Michel, Justine ^{[3
]}

Batut, Aurelie ^{[3
]}

Al Saati, Talal ^{[4
]}

Canlet, Cecile ^{[1
]}

Tremblay-Franco, Marie ^{[1
]}

Ellero-Simatos, Sandrine ^{[1
]}

Langin, Dominique ^{[2
,5
]}

Postic, Catherine ^{[6
]}

Wahli, Walter ^{[1
,7
,8
]}

Loiseau, Nicolas ^{[1
]}

Guillou, Herve ^{[1
]}

Montagner, Alexandra ^{[1
,2
]}

机构：

[1] Paul Sabatier Univ, Univ Toulouse, INP Purpan, Toxalim,INRAE UMR 1331,ENVT, F-31027 Toulouse, France

[2] Paul Sabatier Univ, Inst Natl Sante & Rech Med INSERM, Inst Metab & Cardiovasc Dis, UMR1048,Univ Toulouse, Toulouse, France

[3] Inst Natl Sante & Rech Med INSERM, Metatoul Lipid Facil, MetaboHUB, UMR1048,Inst Metab & Cardiovasc Dis, Toulouse, France

[4] CHU Purpan, Serv Histopathol Expt Unite INSERM, UPS, ENVT US006,CREFRE Inserm, F-31024 Toulouse 3, France

[5] Toulouse Univ Hosp, Lab Clin Biochem, Toulouse, France

[6] Inst Cochin, Inst Natl Sante & Rech Med INSERM, U1016, Paris, France

[7] Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, Clin Sci Bldg,11 Mandalay Rd, Singapore, Singapore

[8] Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland

来源：

SCIENTIFIC REPORTS | 2020年 / 10卷 / 01期

关键词：

ACTIVATED-RECEPTOR-ALPHA; HIGH-FAT DIET; ADIPOSE-TISSUE; ADAPTIVE RESPONSE; LIPID-METABOLISM; GENE-EXPRESSION; LIVER; STEATOHEPATITIS; INFLAMMATION; FIBROSIS;

D O I：

10.1038/s41598-020-63579-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Peroxisome proliferator activated receptor alpha (PPAR alpha) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Ppar alpha in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPAR alpha in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body Ppar alpha (-) deficient mice (Ppar alpha (-/-)) and in mice lacking Ppar alpha only in hepatocytes (Ppar alpha (hep-/-)). We provide evidence that Ppar alpha deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR alpha activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPAR alpha as being essential to the prevention of NAFLD and that extra-hepatocyte PPAR alpha activity contributes to whole-body lipid homeostasis.

引用

页数：15

共 70 条

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