Regulation of hepatocyte lipid metabolism and inflammatory response by 25-hydroxycholesterol and 25-hydroxycholesterol-3-sulfate.
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 IkappaBalpha/NFkappaB 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 TNFalpha-induced inflammatory response by increasing cytoplasmic IkappaBalpha levels, decreasing NFkappaB nuclear translocation, and consequently repressing expression of NFkappaB-dependent genes, IL-1beta, TNFalpha, and TRAF1. NFkappaB-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 IkappaBalpha levels and further increased TNFalpha-induced NFkappaB 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.
Xu
Leyuan
L
Department of Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Research 151, 1201 Broad Rock Blvd, Richmond, VA 23249, USA.
Bai
Qianming
Q
Rodriguez-Agudo
Daniel
D
Hylemon
Phillip B
PB
Heuman
Douglas M
DM
Pandak
William M
WM
Ren
Shunlin
S
D000818:Animals; D002788:Cholesterol Esters / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D018836:Inflammation Mediators; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D051780:Sterol Regulatory Element Binding Protein 1; D000097782:NF-kappaB-Inducing Kinase; C534977:25-hydroxycholesterol 3-sulfate; C007997:25-hydroxycholesterol