Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4α Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis

Abstract

The cholesterol sulfotransferase SULT2B1b converts cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, downregulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4α upon fasting, and the Sult2B1b null (Sult2B1b) mice showed increased gluconeogenic gene expression and an elevated fasting glucose level, suggesting that SULT2B1b also plays a restrictive role in HNF4α-mediated fasting-responsive gluconeogenesis. We also developed thiocholesterol, a hydrolysis-resistant derivative of CS, which showed superior activity to that of the native CS in inhibiting gluconeogenesis and improving insulin sensitivity in high-fat-diet-induced diabetic mice. We conclude that the HNF4α-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia.

An Unexpected Role of Cholesterol Sulfotransferase and its Regulation in Sensitizing Mice to Acetaminophen-Induced Liver Injury

“…Overexpression of Hnf4a Induces Sult2B1b and Sensitizes Mice or Primary Hepatocytes to APAP-Induced Injury. We recently reported that Sult2B1b is a transcriptional target of Hnf4a (Bi et al, 2018). Having shown that overexpression of SULT2B1b sufficed to sensitize mice to APAP-induced liver injury, we wanted to determine whether upregulation of Sult2B1b by HNF4a in the mouse liver will have a similar sensitizing effect on APAP-induced liver injury.…”

“…Mechanistically, SULT2B1b and its enzymatic product cholesterol sulfate suppress gluconeogenesis by inhibiting acetyl-CoA synthetase gene expression, leading to reduced acetylation and nuclear exclusion of HNF4a (Shi et al, 2014). More recently, we reported that the SULT2B1b itself is a transcriptional target gene of HNF4a (Bi et al, 2018). The establishment of SULT2B1b as a HNF4a target gene called up our hypothesis that the induction of SULT2B1b by HNF4a involves in a negative feedback to inhibit the gluconeogenic activity of HNF4a (Bi et al, 2018).…”

“…More recently, we reported that the SULT2B1b itself is a transcriptional target gene of HNF4a (Bi et al, 2018). The establishment of SULT2B1b as a HNF4a target gene called up our hypothesis that the induction of SULT2B1b by HNF4a involves in a negative feedback to inhibit the gluconeogenic activity of HNF4a (Bi et al, 2018). Although several SULT isoforms and their regulations have been implicated in APAP toxicity (Saini et al, 2011), it is unknown whether SULT2B1b plays a role in APAP hepatotoxicity and, if so, whether HNF4a can also impact the hepatotoxicity of APAP by its positive regulation of SULT2B1b.…”

Prognostic Effect of Preoperative Apolipoprotein B Level in Surgical Patients with Renal Clear Cell Carcinoma

“…Subsequently, some experimental studies also confirmed the above result and further found that the level of cholesterol was positively associated with the malignant degree of cancer cells [16,17]. However, the cholesterol levels in advanced biological cells are maintained in a fairly narrow range, and the negative feedback regulation of endogenous cholesterol synthesis play an important role in maintaining the cholesterol metabolic balance [18,19]. And the biological effect of serum cholesterol was related with low-density lipoprotein (LDL) [20].…”

Opposing steroid signals modulate protein homeostasis through deep changes in fat metabolism in Caenorhabditis elegans

“…The activity of both sulfotransferases and sulfatases regulates signalling via nuclear hormone receptors (NHR), by adding or removing a sulfate moiety to hormones, or their precursors (reviewed by He et al, 25 ). Inversely, NHRs are able to modulate the expression of genes encoding these enzymes, through negative feedback loops operated by their enzymatic products 26 . Interestingly, Burton and co-workers showed that the C. elegans sulfotransferase SSU-1 controls hormonal signalling through NHR-1 to regulate insulin sensitivity and specificity 27 .…”