ChREBP Regulation in Rattus norvegicus
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ChREBP Regulation in Rattus norvegicus

The liver is the major organ responsible for the conversion of excess dietary carbohydrate into triglycerides. Ins (Insulin) and Glucagon (a pancreatic hormone) play critical roles in homeostatsis of Glucose and triglycerides in humans as well as in R. norvegicus (Rattus norvegicus). Glucose serves as a signal independent of hormones in activation of more than 15 enzyme genes in the lipogenic pathways. However, the mechanism by which Glucose generates signal to induce these gene is not known (Ref.1). Ingestion of a high carbohydrate diet leads to the activation of several regulatory enzymes of Glycolysis and Lipogenesis, including the PKLR (Pyruvate Kinase, Liver and RBC), also known as LPK (L-Type Pyruvate Kinase). The lipogenic genes contain ChREs (Carbohydrate Responsive Elements) within their promoters that mediate Glucose responsiveness. The ChREBP (Carbohydrate Responsive Element Binding Protein) is a liver specific transcrpiton factor, which bind to the ChRE region in the lipogenic genes and helps in the expression of PKLR (Ref.2). The rat ChREBP is a large protein (865 amino acids) and contains several functional domains including NLS (Nuclear Localization Signal), a bHLH/Zip (basic Helix-Loop-Helix-Leucine Zipper) for DNA binding and a Zip-like (Leucine Zipper-like) domain. In addition, it contains several potential phosphorylation sites for cAMP (Cyclic Adenosine Monophosphate)-dependent PKA (Protein Kinase-A) and AMPK (AMP-Activated Protein Kinase) (Ref.3).

In R. norvegicus, ChREBP is regulated at two levels, nuclear entry and DNA binding, by phosphorylation-dependent mechanism in response to Glucagon (or hormones), cAMP, Fatty Acids and Glucose. In the presence of cAMP, a site near the NLS, Ser196 (Serine-196) is phosphorylated by PKA and ChREBP being unable to enter the nucleus, remains in cytosol. cAMP also inactivates DNA binding activity of ChREBP by PKA catalyzed phosphorylation of the bHLH/Zip domain, Thr666 (Threonine-666). Free Fatty Acids increases AMP (Adenosine 5-Monophosphate) concentration in liver which activates AMPK, an important protein kinase in fat metabolism (Ref.4). ChREBP is phosphorylated by AMPK near the bHLH/Zip site (Ser568) which inactivates the DNA binding activity and inhibits the lipogenic gene transcription. AMPK is activated by the increased AMP, which likely results from Fatty Acid activation by rat ACS (Acyl-CoA Synthase) along with CoA (Coenzyme A or CoASH) and ATP (Adenosine Triphosphate). In this process Acyl-CoA (or ROC-CoA) and PPi (Inogranic Pyrophosphate) are released out.  Thus in general there appear to be two levels of regulation of ChREBP by PKA-mediated phosphorylation as a result of rise in cAMP. One is the phosphorylation of Ser196, which inhibits nuclear import and the other is Thr666, which inhibits the DNA-binding activity (Ref.5 & 6).

Glucose counteracts all these negative effect on ChREBP produced by hormones, cAMP and Fatty Acids. Glucose is able to reverse these inhibitory effects at both levels. The simplest mechanism for this reversal is by dephosphorylation of these phosphorylation sites by PP2A (Protein Phosphatase-2A) (Ref.6). PP2A is activated in liver by high Glucose. But conditions like starvation, hypoxia, heat shock etc., inhibit PP2A function. The Glucose-signaling compound, Xu-5-P (Xylulose-5-Phosphate), specifically activates PP2A. Xu-5-P is the signaling metabolite for Glucose activation of Glycolysis. Xu-5-P activated PP2A is involved in the activation of both nuclear transport and the DNA-binding activities of ChREBP. ChREBP also plays an essential role(s) in the regulation of a number of other genes, besides PKLR, involved in glucose and lipid metabolism (Ref.7).