Regulation by Absolute Changes in Protein HMGCS2 Concentration

At the genetic level HMGCS2 gene expression is upregulated by glucocorticoids, fatty acids, and cyclic adenosine monophosphate (cAMP) and downregulated by insulin

HMGCS2 promoter

Fig. 3. The HMGCS2 gene promoter. The promoter region is depicted by an open box for the DNA sequence upstream of the transcription start site tss and a solid box for the transcribed region downstream of the transcription start site. Abbreviations for DNA sequence elements and receptors: GRE, glucocorticoid response element; CRE, cAMP response element; IRE, insulin response element; PPRE, peroxisome proliferator response element; GR, glucocorticoid receptor; RXR, retinoid X receptor. Abbreviations for signals that regulate HMGCS2 gene expression: GCs, glucocorticoids; cAMP, cyclic AMP; INS, insulin; FAs, fatty acids. Also depicted is the relationship between the nucleus (N), cytosol (C), and mitochondria (M), in terms of the dual actions of HMGCS2 as an enzyme generating ketone bodies (KBs) from acetyl-CoA (Ac-CoA) and as a transcription cofactor (see text).

HMGCS2 promoter

Fig. 3. The HMGCS2 gene promoter. The promoter region is depicted by an open box for the DNA sequence upstream of the transcription start site tss and a solid box for the transcribed region downstream of the transcription start site. Abbreviations for DNA sequence elements and receptors: GRE, glucocorticoid response element; CRE, cAMP response element; IRE, insulin response element; PPRE, peroxisome proliferator response element; GR, glucocorticoid receptor; RXR, retinoid X receptor. Abbreviations for signals that regulate HMGCS2 gene expression: GCs, glucocorticoids; cAMP, cyclic AMP; INS, insulin; FAs, fatty acids. Also depicted is the relationship between the nucleus (N), cytosol (C), and mitochondria (M), in terms of the dual actions of HMGCS2 as an enzyme generating ketone bodies (KBs) from acetyl-CoA (Ac-CoA) and as a transcription cofactor (see text).

(8). Thus, the promoter region of the HMGCS2 gene (Fig. 3) contains DNA response elements (8) mediating the action of fatty acids (peroxisome proliferator response element, PPRE), insulin (insulin response element, IRE), glucagon (cAMP response element, CRE) and glucocorticoids (glucocorticoid response element, GRE). The HMGCS2 PRRE binds PPARa, always in combination with another nuclear receptor, the retinoid X receptor (RXR) (Fig. 3), which is activated by retinoids (8,16). Furthermore, in a superb demonstration of nature's ingenuity, Meertens and others have shown that HMGCS2 protein has a second role as a transcription factor coactivator of PPARa that selectively activates expression of the HMGCS2 gene itself (Fig. 3) (17). This may occur via the acetyltransferase activity of HMGCS2, resulting in changes in the ratio of acetylated/deacetylated nuclear histone proteins that regulate access of transcription factors such as PPARa to the HMGCS2 gene promoter (17,18). Thus, changes in cellular concentrations of acetyl-CoA resulting from fatty acid oxidation will alter the ratio of acetylated to deacetylated HMGCS2. Upon translocation to the nucleus, the ratio of acetylated to deacetylated HMGCS2 molecules would then determine their capacity to acetylate/deacetylate histone proteins bound to the promoter of the HMGCS2 gene. In its dual role as an enzyme and PPARa transcription cofactor, HMGCS2 protein may thus act as a messenger in the cellular dialog between the nucleus and the mitochondrion, critical to controlling intracellular acetyl-CoA concentrations (17).

In terms of its importance in regulation of FAOK, of the three FAOK regulatory enzymes, i.e., ACS1, CPTla, and HMGCS2, only HMGCS2 lies downstream of acetyl-CoA, the critical moiety for the formation of ketone bodies (Fig. 1). Moreover, the critical regulatory role of HMGCS2 in FAOK is reflected in the observation that fatty acid oxidation can be inhibited, by end-product inhibition at several enzyme steps if acetyl-CoA concentrations are allowed to build up in the mitochondrion. Thus, the intimate formation of a PPARa/HMGCS2 transcription complex, which selectively activates transcription of HMGCS2 at the expense of other PPARa-activated genes (17), suggests that upregulation of HMGCS2 expression is of paramount importance in the fatty acid "hormone" regulation of the FAOK pathway.

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