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Additional mechanisms of glucose-mediated regulation of ChREBP activity were made apparent when it was shown that mutations in the PKA phosphorylation sites (S196 and T666) did not completely abolish glucose-responsiveness. Further analysis of ChREBP regulation in response to glucose administration was shown to be due to domains present in the amino terminal portion of ChREBP. The glucose sensing domain (GSM) is actually composed of two distinct sub-domains identified as the low-glucose inhibitory domain (LID) and the glucose-responsive activation conserved element (GRACE). Under conditions of low glucose the LID inhibits transcriptional transactivation by the GRACE domain. This inhibition is reversed by glucose or a glucose metabolite.

Recently a newly discovered mechanism of regulated ChREBP activity involves the tissue-specific transcription of an alternatively spliced form of ChREBP. This alternative splice variant contains a novel upstream exon (identified as exon 1b) and bypasses the originally identified exon 1 (now identified as exon 1a). This novel mechanism of ChREBP activity has been shown to occur in adipose tissue and represents a potent mechanism for glucose-mediated modulation of adipose tissue fatty acid synthesis and insulin sensitivity. The original ChREBP is now referred to as ChREBP-α and the novel alternative splice form is called ChREBP-β. The means by which glucose plays a role in adipose tissue ChREBP activity is that glucose, or a metabolite, activates the transcriptional activity of ChREBP-α by the mechanisms described earlier. Then, one of the important adipose tissue targets for glucose-activated ChREBP-α is the upstream transcriptional activation site that regulates the transcription of ChREBP-β. Following adipose tissue activation of ChREBP-β expression, both ChREBP-α and ChREBP-β work in concert to dramatically alter lipogenic gene expression.

Genes whose patterns of expression are under the control of ChREBP activity include L-PK, ACC1 and FAS as indicated above. As indicated, within adipose tissue ChREBP-α and ChREBP-β function together to dramatically increase the transcription of lipogenic genes in this tissue such as FAS and ACC1. In addition, it has been shown that when expression of ChREBP is reduced the expression levels of glycerol 3-phosphate acyltransferases, GPAT (encoded by four distinct genes: GPAM, GPAT2, GPAT3, GPAT4) and Δ 9 -stearoly-CoA desaturase 1 (SCD1) are also reduced. The GPAT enzymes esterify glycerol-3-phospate generating lysophosphatidic acid (LPA) which is the first step in the synthesis of triacylglycerides (TAGs) as described below . SCD1 is the rate-limiting enzyme involved in the synthesis of the major monounsaturated fatty acids oleic acid (18:1) and palmitoleic acid (16:1) as described below in the section on Elongation and Desaturation.

The liver X receptors (LXRs) are members of the steroid/thyroid hormone superfamily of cytosolic ligand binding receptors that migrate to the nucleus upon ligand binding and regulate gene expression by binding to specific target sequences. There are two forms of the LXRs, LXRα and LXRβ. The LXRs form heterodimers with the retinoid X receptors (RXRs) and as such can regulate gene expression either upon binding oxysterols (e.g. 22 R -hydroxycholesterol) or 9- cis -retinoic acid. LXRs are also important regulators of the lipogenic pathway. Recent evidence has demonstrated that the ChREBP gene is a direct target of LXRs and that glucose itself can bind and activate LXRs.

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about a month ago

Mr. Sen, you are an extraordinary writer. Excellent craftsmanship. Congratulations on your award. Very well deserved. As to being able to find out what happened to her, along with the suggestions about checking with musicians that may have known her, it seems to me that she probably has family in her hometown (according to the account, she had an uncle) or descendants of her family that would have some knowledge of what happened to her. May be a good idea to look there.

about a month ago Chuck Danas

I had the honor of eating there in 1992 with the production staff at Comedy Central. This article brought back such wonderful memories of that wonderful place and now realizing I was also honored to hear her sing and play the piano, that night as well. I remember one of us kept running out to buy more wine. The food was absolutely the best soul food dinner of my life, It was a wonderful time that I will always treasure. Thank you for the article!!!

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