Dataset Information

Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH.

ABSTRACT: Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.

SUBMITTER: Cariello M

PROVIDER: S-EPMC8042405 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH.

Cariello Marica M Piccinin Elena E Moschetta Antonio A

Cellular and molecular gastroenterology and hepatology 20210202 5

Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of ...[more]

PMID: 33545430

Similar Datasets

Project description:The farnesoid X receptor (FXR) is known to regulate the gene expression of SR‑BI, which mediates plasma high‑density lipoprotein (HDL)‑cholesterol uptake. Our previous study demonstrated that the activation of FXR by obeticholic acid (OCA) lowered plasma HDL‑cholesterol levels and increased the hepatic mRNA and protein expression levels of SR‑BI in hypercholesterolemic hamsters, but not in normolipidemic hamsters, suggesting that dietary cholesterol may be involved in the OCA‑induced transcription of SR‑BI. In the present study, a functional 90‑base‑pair regulatory region was identified in the first intron of the SR‑BI gene of hamster and mouse that contains a FXR response element (IR‑1) and an adjacent liver X receptor (LXR) response element (LXRE). By in vitro DNA binding and luciferase reporter gene assays, it was demonstrated that FXR and LXR bind to their recognition sequences within this intronic region and transactivate the SR‑BI reporter gene in a synergistic manner. It was also shown that mutations at either the IR‑1 site or the LXRE site eliminated OCA‑mediated gene transcription. Utilizing chow‑fed hamsters as an in vivo model, it was demonstrated that treating normolipidemic hamsters with OCA or GW3965 alone did not effectively induce levels of SR‑BI, whereas their combined treatment significantly increased the mRNA and protein levels of SR‑BI in the liver. The study further investigated effects of FXR and LXR coactivation on the gene expression of SR‑BI in human liver cells. The intronic FXRE and LXRE regulatory region was not conserved in the human SR‑BI genomic sequence, however, higher mRNA expression levels of SR‑BI were observed in human primary hepatocytes and HepG2 cells exposed to combined treatments of FXR and LXR agonists, compared with those in cells exposed to individual ligand treatment. Therefore, these results suggest that human SR‑BI gene transcription may also be subject to concerted activation by FXR and LXR, mediated via currently unidentified regulatory sequences.

Dataset Information

Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH.

Publications

Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets