Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α

Abstract

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders

“… 46 Moreover, HNF-1 repressed the expression of SigR1 to restrain the formation of lipid droplets in adipocytes, impeding adipogenesis and adipocyte hypertrophy. 49 HNF-1β enhanced the oxidative function of mitochondria and facilitated adipolysis by restraining A1254-influenced expression, stunting the development of obesity. 51 Additionally, HNF-1 suppressed excessive accumulation of lipids, such as TG, in white adipose tissue and significantly reduced obesity, which impairs physical health.…”

“… 6 HNF-1α restrained the expression of sigma receptor 1 (SigR1) to reduce lipid droplet formation and storage capacity of neutral lipids in HepG2 and Huh7 cells, eventually preventing hepatic steatosis in hepatocellular adenoma. 49 Dipeptidyl peptidase 4 (DPP4)/nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) enhances the production of TG and the formation of lipid droplets in hepatocytes. HNF-1β binding to the promoters of DPP4 and NOX1 weakened the expression of these genes to restore hepatic TG homeostasis and alleviate liver injury and insulin resistance in C57BL/6J mice.…”

Estrobolome and Hepatocellular Adenomas—Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link

“…Sigma receptor 1 (Sig-R1) represents a membrane protein that belongs to the endoplasmic reticulum as a component of the mitochondria-associated membrane (MAM) region [43]. It is linked to one of the multifunctional characteristics of the endoplasmic reticulum, which is a response to stress with neuronal protective activity, while Sig-R1 balances the production of reactive oxygen species at the mitochondrial level [44].…”

Role of Sigma-1 Receptor in Calcium Modulation: Possible Involvement in Cancer

“…A more recent study revealed an S1R overexpression in hepatocellular adenomas (HCA) compared to non-tumoral liver and demonstrated that this is mediated by estrogen receptor (ERα) transcriptional activity and correlates with loss of function of transcription repressor hepatocyte nuclear factor 1a (HNF1α). Indeed, S1R overexpression is higher among the HCA subtypes that present bi-allelic mutations of HNF1α, which is mostly found in women that are under treatment with estrogen [ 80 ].…”

“…In hepatocellular adenomas S1R promotes not only proliferation but also lipid accumulation, suggesting that it is involved in the induction of steatosis, a peculiar characteristic of this type of tumor [ 80 ]. Indeed, MAMs are an important site for lipid metabolism and the S1R receptor has been shown to play a role in this context by mediating the induction of lipogenesis [ 89 , 90 ].…”