Transcriptional regulation of mitochondrial glycerophosphate acyltransferase is mediated by distal promoter via ChREBP and SREBP-1

Abstract

We have recently identified two promoters, distal and proximal for rat mitochondrial glycerophosphate acyltransferase (mtGPAT). Here we are reporting further characterization of the promoters. Insulin and epidermal growth factor (EGF) stimulated while leptin and glucagon inhibited the luciferase activity of the distal promoter and the amounts of the distal transcript. Conversely, luciferase activity of the proximal promoter and proximal transcript remained unchanged due to these treatments. Only the distal promoter has binding sites for carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein-1 (SREBP-1). Electromobility shift assays and chromatin immunoprecipitation assays demonstrated that ChREBP and SREBP-1 bind to the mtGPAT distal promoter. Insulin and EGF increased while glucagon and leptin decreased the binding of SREBP-1 and ChREBP to the distal promoter. Thus, the distal promoter is the regulatory promoter while the proximal promoter acts constitutively for rat mtGPAT gene under the influence of hormones and growth factor.

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

“…Indeed, ChREBP overexpression induced, the entire lipogenic/esterification program in liver independently of an increase in SREBP-1c activity and/or LXRα expression. Aside from previously known targets of ChREBP, such as L-PK, ACACA, FASN, GPAT, G6PC, and FGF21 (19,34,52), our results reveal that SCD1 and Elovl6 are key ChREBP target genes. Indeed, a selective enrichment in their lipid products (i.e., MUFA) ( Figure 2G) was observed upon ChREBP overexpression in liver under both standard and HFDs.…”

Hepatic Fatty Acid Trafficking: Multiple Forks in the Road

“…ER stress also increases SREBP1c activity leading to elevated DNL and may be an important contributor to the elevated DNL observed in individuals with NAFLD (151,152). Glucose and/or fructose drive DNL by providing substrates for DNL and by upregulating carbohydrate response element binding protein (CHREBP), which in turn increases the transcription of genes involved in glycolysis, DNL, and TG synthesis (153)(154)(155). Fructose is especially lipogenic due to its very rapid flux into the liver and its ability to bypass key regulatory steps in glycolysis [see (156) for review].…”

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…SREBP (sterol response element binding protein), ChREBP (carbohydrate response element binding protein), SP1, and CTF1 binding sites are present in the distal promoter region, whereas hepatocyte nuclear factor (HNF-1 and HNF-4), NFκB, NFY binding reverse CAAT box, activating protein binding site (AP1 and AP4), myocyte enhancer factor (MEF2), upstream stimulatory factor (USF), and matrix attachment regions (MARS) are present in the proximal promoter. Insulin and glucose activate the binding of ChREBP to promote Gpat1 transcription, and EGF and LXRα stimulate the binding of SREBP-1 to sterol response elements to increase Gpat1 expression [134]. On the other hand, glucagon and leptin exert inhibitory effects [134].…”

“…Insulin and glucose activate the binding of ChREBP to promote Gpat1 transcription, and EGF and LXRα stimulate the binding of SREBP-1 to sterol response elements to increase Gpat1 expression [134]. On the other hand, glucagon and leptin exert inhibitory effects [134]. …”