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Nutrients 2018, 10(11), 1699; https://doi.org/10.3390/nu10111699

ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners

1
Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
2
Gifu University Hospital Center for Nutritional Support and Infection Control, Gifu 501-1194, Japan
3
Koseikai Takeda Hospital, Shimogyo-ku, Kyoto 600-8558, Japan
*
Author to whom correspondence should be addressed.
Received: 20 October 2018 / Revised: 1 November 2018 / Accepted: 5 November 2018 / Published: 7 November 2018
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Abstract

Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia. View Full-Text
Keywords: Chrebp; carbohydrate response element-binding protein; fatty liver; Fgf21; fibroblast growth factor 21; Angptl3; angiopoietin-like 3; Angptl8; angiopoietin-like 8 Chrebp; carbohydrate response element-binding protein; fatty liver; Fgf21; fibroblast growth factor 21; Angptl3; angiopoietin-like 3; Angptl8; angiopoietin-like 8
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Iizuka, K.; Takao, K.; Kato, T.; Horikawa, Y.; Takeda, J. ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners. Nutrients 2018, 10, 1699.

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