Factors That Control the Tissue-Specific Transcription of the Gene for Phosphoenolpyruvate Carboxykinase-C

Abstract

Transcription of the gene for PEPCK-C occurs in a number of mammalian tissues, with highest expression occurring in the liver, kidney cortex, and white and brown adipose tissue. Several hormones and other factors, including glucagon, epinephrine, insulin, glucocorticoids and metabolic acidosis, control this process in three responsive tissues, liver, adipose tissue, and kidney cortex. Expression of the gene in these three tissues in regulated in a different manner, responding to the specific physiological role of the tissue. The PEPCK-C gene promoter has been extensively studied and a number of regulatory regions identified that bind key transcription factors and render the gene responsive to hormonal and dietary stimuli. This review will focus on the control of transcription for the gene, with special emphasis on our current understanding of the transcription factors that are involved in the response of PEPCK-C gene in specific tissues. We have also reviewed the biological function of PEPCK-C in each of the tissues discussed in this review, in order to place the control of PEPCK-C gene transcription in the appropriate physiological context. Because of its extraordinary importance in mammalian metabolism and its broad pattern of tissue-specific expression, the PEPCK-C gene has become a model for studying the biological basis of the control of gene transcription.

Signalling mechanisms linking hepatic glucose and lipid metabolism

“…Induction of AMPK in hepatoma cells also decreases PEPCK and G-6-Pase transcription, likely in an insulin-independent manner [104]. AMPK is not known to be activated by insulin, raising the possibility that insulin and AMPK regulate PEPCK by different and, perhaps, converging pathways [70]. AMPK may prevent insulin resistance in part by inhibiting factors that antagonise insulin signalling [100].…”

“…SREBP-1c and SREBP-2 are the predominant subtypes in the rodent and human liver [67]. The main role of SREBP-2 is cholesterol synthesis, whereas SREBP-1c activates a complete programme of hepatic fatty acid synthesis [68] and reciprocally inhibits the expression of the gene for PEPCK when carbohydrates are abundant [69,70]. Overexpression of the gene for SREBP-1c leads to fatty liver in mice [71].…”

“…Glucocorticoids stimulate the transcription of glucogenic genes (including those for PEPCK and G-6-Pase [70,93]), inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid β-oxidation, and may produce fatty liver in humans [94]. In Cushing's syndrome, increased glucocorticoid production and activation of the glucocorticoid receptor leads to obesity and insulin resistance.…”

A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects

“…The compensatory upregulation of G6pc on PP1was ineffectual because there were little glycogen reserves upon which the enzyme could act. The up-regulation of liver Pck1, whose product is the rate limiting step of gluconeogenesis from non-carbohydrate sources (Chakravarty et al 2005), on E19 and PP1 was also insufficient to alleviate the hypoglycemia. We also observed a dramatic depletion of lipid stores in BAT and the reduced expression of two BAT-specific thermogenic genes, Pgc1a and Ucp1.…”

Role of β‐catenin in the adult liver†‡

“…For example, the gene encoding phosphoenolpyruvate carboxykinase (PEPCK), expressed in liver and other tissues, has upstream cis-elements for several transcription factors and is under complex, tissue-specific and hormone-dependent control in keeping with its critical role in gluconeogenesis. 16 While little information exists on the mechanism of regulation of Glu1, earlier studies using in vitro transcription 17 and analysis of HNF1␣-null mice 18 revealed that the Cyp2e1 gene is controlled by the liver-enriched transcription factor HNF1␣. Expression of the gene encoding CYP1A2 is also controlled by HNF1␣ as well as other transcription factors.…”