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

Abstract

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

“…ACLY gene expression is positively regulated by the SREBP-1 (sterol regulatory element binding protein-1) and ChREBP (carbohydrate response element binding protein) transcriptional regulators [ 43 ]. In several tissues such as liver and white adipose tissue, ACLY gene expression is downregulated when lipid synthesis is low such as during fasting, CR, or low carbohydrate, high-fat diets [ 44 , 45 ].…”

“…Similar to the transcriptional regulation of ACLY, ACSS2 gene expression in liver, adipose, and intestine is controlled by ChREBP [ 43 ], while SREBPs also play an important role [ 71 ]. There are also Sp1 and Sp3 binding sites in the ACSS2 promoter [ 72 ].…”

Atractylodes chinensis Water Extract Ameliorates Obesity via Promotion of the SIRT1/AMPK Expression in High-Fat Diet-Induced Obese Mice

“…The physiological role of SREBP1 in response to nutrition was initially proposed for the modulation of lipogenic genes, such as FAS, in adipose tissue and liver [ 27 ]. Furthermore, ChREBP controls fatty acid synthesis, elongation, and desaturation by promoting FAS and ACC1 [ 28 ]. Our results showed that Ac administration diminished the expression of the lipogenic genes SREBP1, Chrebp, and FAS in the eWAT of the HFD-induced obese mouse model ( Figure 4 B).…”

Protein Co-expression Network-based Profiles Revealed from Laser-microdissected Cancerous Cells of Lung Squamous-Cell Carcinomas

“…MYCN, a member of the MYC family of oncogenes, also encodes a bHLH-LZ protein MYCN, and its deregulation was reported in various cancer types and was often associated with a poor prognosis. MYCN-ampli ed cancer cells exhibit the enhanced expression of genes and proteins involved in aerobic glycolysis (referred to as the Warburg effect), oxidative phosphorylation, and the detoxi cation of reactive oxygen species (ROS) [52]. Numerous chemical drug interventions including sirolimus (rapamycin) were inhibited (Table 2), suggesting an involvement of potential therapeutic targets in those datadriven networks.…”