Journal Article

Regulation of Hepatocyte Lipid Metabolism and Inflammatory Response by 25-Hydroxycholesterol and 25-Hydroxycholesterol-3-sulfate

Hylemon, Phillip B, Heuman, Douglas M, Xu, Leyuan, Pandak, William M, Bai, Qianming, Rodriguez-Agudo, Daniel, Ren, Shunlin

2010

Overview

Dysregulation of lipid metabolism is frequently associated with inflammatory conditions. The mechanism of this association is still not clearly defined. Recently, we identified a nuclear oxysterol, 25-hydroxycholesterol-3-sulfate (25HC3S), as an important regulatory molecule involved in lipid metabolism in hepatocytes. The present study shows that 25HC3S and its precursor, 25-hydroxycholesterol (25HC), diametrically regulate lipid metabolism and inflammatory response via LXR/SREBP-1 and IκBα/NFκB signaling in hepatocytes. Addition of 25HC3S to primary rat hepatocytes decreased nuclear LXR and SREBP-1 protein levels, down-regulated their target genes, acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and SREBP-2 target gene HMG reductase, key enzymes involved in fatty acid and cholesterol biosynthesis. 25HC3S reduced TNFα-induced inflammatory response by increasing cytoplasmic IκBα levels, decreasing NFκB nuclear translocation, and consequently repressing expression of NFκB-dependent genes, IL-1β, TNFα, and TRAF1. NFκB-dependent promoter reporter gene assay showed that 25HC3S suppressed luciferase activity in the hepatocytes. In contrast, 25HC elicited opposite effects by increasing nuclear LXR and SREBP-1 protein levels, and by increasing ACC1 and FAS mRNA levels. 25HC also decreased cytoplasmic IκBα levels and further increased TNFα-induced NFκB activation. The current findings suggest that 25HC and 25HC3S serve as potent regulators in cross-talk of lipid metabolism and inflammatory response in the hepatocytes.

• Publisher: Berlin/Heidelberg : Springer-Verlag,Springer-Verlag,Springer‐Verlag,Springer Nature B.V
• Subject: acetyl-CoA carboxylase / Animals / Biomedical and Life Sciences / Biosynthesis / cholesterol / Cholesterol Esters - pharmacology / Dose-Response Relationship, Drug / Fatty acids / fatty-acid synthase / gene expression regulation / hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Hydroxycholesterols - pharmacology / IKappaB kinase / inflammation / Inflammation Mediators - metabolism / Inflammatory response / interleukin-1beta / IκBα / Life Sciences / Lipid metabolism / Lipid Metabolism - drug effects / Lipidology / Liver - drug effects / Liver - metabolism / luciferase / LXR / Medical Biochemistry / Medicinal Chemistry / messenger RNA / Microbial Genetics and Genomics / Neurochemistry / NF-kappaB-Inducing Kinase / NFκB / Nuclear orphan receptor / Nutrition / Original Article / Oxysterol metabolism / Oxysterol sulfation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Rats / Receptors, Retinoic Acid - genetics / Receptors, Retinoic Acid - metabolism / reporter genes / RNA, Messenger - metabolism / Sterol Regulatory Element Binding Protein 1 - genetics / Sterol Regulatory Element Binding Protein 1 - metabolism / Sulfates / transcription factor NF-kappa B / Translocation / tumor necrosis factor-alpha