ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners

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.

Effects of Moderate Chronic Food Restriction on the Development of Postprandial Dyslipidemia with Ageing

“…Accordingly, we hypothesized that liver from 24mFR rats could produce a molecular switcher, which determines browning of white adipocytes and overstimulates postprandial thermogenesis to dissipate energy as heat. Similar findings were reported in adenovirus-ChREBP-β-infected mice, although herein we observed that circulating levels of FGF21 did not increase in the 24mFR rats as in adenovirus-ChREBP-β-infected mice [58]. Hence, our findings support the notion that FGF21 acts in an autocrine/paracrine manner in vWAT from aged rats, overstimulating the postprandial thermogenic adaptive responses, as described [59].…”

ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

“…The hepatic Mtp mRNA expression of mice with hepatic Chrebp overexpression is similar to that of control mice (32). Because hepatic Chrebp overexpression reduces the concentrations of VLDL-triglycerides and lowdensity lipoprotein-triglycerides (32), it has been suggested that lipoprotein lipase (LPL) might be activated by hepatic Chrebp overexpression. Consistent with this, we found that hepatic Chrebp overexpression increased hepatic Fgf21 mRNA expression and the plasma FGF21 concentration (20,32,57).…”

“…In addition, ChREBP plays a critical role in the conversion of gut microbiota-derived acetate, the production of which is increased by excess dietary fructose intake, to acetyl coenzyme A (CoA) by activating its target, Acss2, in the liver, which contributes to hepatic triglyceride accumulation (29). ChREBP also modulates hepatic b-oxidation and ketogenesis (30)(31)(32). This review focuses on recent advances in knowledge of the ChREBP-mediated regulation of lipid metabolism in the liver, adipose tissue, and gut.…”

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

“…During feeding, serum glucose and insulin secretion enhance ANGPTL8 expression, in both adipocytes and hepatocytes [ 91 ]. A specific transcription factor for ANGPTL8 is the carbohydrate-responsive element-binding protein (ChREBP), which is induced by insulin stimulation [ 91 ]. While hepatocyte-derived ANGPTL8 is mainly secreted, in WAT and BAT it remains in nucleoplasm [ 69 ].…”

“…In conditions of chronic overnutrition, both serum insulin and glucocorticoid levels increase, leading to a change in ANGPTL system homeostasis: chronic overexpression of ANGPTL8 in hepatocytes may determine augmented insulin resistance, lipogenesis, increased VLDL secretion, and liver steatosis [ 68 , 91 ]. In WAT, the co-expression of ANGPTL4 and ANGPTL8 may determine enhanced adipose tissue inflammation and uncontrolled expansion leading to adipocytes dysfunction [ 35 , 88 , 91 ]. In this context, BAT may be also affected, since a chronic overexpression of ANGPTL8 reduces PPARs and UCP1 expression favoring lipogenesis and BAT whitening [ 51 ] ( Figure 2 ).…”