Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

Abstract

Abstract. Carbohydrate response element binding protein (ChREBP) is a transcription factor activated by glucose that is highly expressed in liver, pancreatic β-cells, brown and white adipose tissues, and muscle. We reported that hepatic suppression of the Chrebp gene improves hepatic steatosis, glucose intolerance, and obesity in genetically obese mice. Moreover, we have studied the role of ChREBP with special reference to feedforward and feedback looping in liver and pancreatic β-cells. Recently, several groups reported that (1) glucose activates ChREBP-α transactivity and in turn ChREBP-α induces ChREBP-β on both transcriptional and translational levels in adipose tissues, and (2) ChREBP regulates glucose transporter type 4 mRNA levels, which may affect glucose uptake in adipose tissues. Moreover, in adipose tissues of obese patients, Chrebpb mRNA levels were much lower than those in lean subjects, while the levels were much higher in liver of obese patients than those in lean subjects. These findings suggest that Chrebpb mRNA levels are different in various tissues and probably in the stages of diabetes mellitus. Herein, we review recent progress in the study of ChREBP with special references to (1) the mechanisms regulating ChREBP transactivity (posttranslational modifications, intramolecular glucose sensing module, feedforward mechanism, and the feedback loop between ChREBP and its target genes), and (2) the role of ChREBP in liver, pancreatic islets and adipose tissues. Understanding the role of ChREBP in each tissue will provide important insight into the pathogenesis of metabolic syndrome.

Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors

“…5C ), a reported modifi cation that results in higher ChREBP nuclear translocation and transcriptional activity ( 37 ). Detailed studies of the posttranslational modifi cation and transcriptional coregulators associated with ChREBP will be necessary to completely understand the actions of leptin on the transcriptional control of hepatic lipogenesis ( 54,55 ). Unlike the lipodystrophic A-ZIP/F-1 mice ( 43 ), Agpat2…”

Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms

“…At transcriptional level, lipid synthesis is regulated by sterol regulatory element-binding proteins (SREBPs) [58] and carbohydrate response element binding protein (ChREBP) [59], which are considered the most important lipogenic transcription factors. SREBPs belong to a family of transcription factors including SREBP-1a, SREBP-1c and SREBP-2 that are involved in the control of lipid homeostasis through the regulation of several genes [58].…”

“…ChREBP is a glucose-sensitive transcription factor controlling the conversion of carbohydrates into lipids in the liver [59]. ChREBP is a bZIP transcription factor that forms a heterodimeric complex with another bZIP protein max-like protein X (MLX) [59].…”

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

“…GPAT1 prefers to acylate saturated fatty acids like 16:0 (8), but GPAT4 has minimal fatty acid preference (6). However, culturing primary hepatocytes in a high-glucose medium probably stimulates de novo fatty acid synthesis via ChREBP, thereby enhancing the cellular content of 16:0 fatty acids (15). In contrast, free-living rodents fed chow or a safflower diet would have different fatty acids available for lipid synthesis (22,24).…”