title: Novel modulators of hepatosteatosis, inflammation and fibrogenesis.
abstract: Alcoholic steatosis, instead of being innocuous, plays a critical role in liver inflammation and fibrogenesis. The severity of fatty liver is governed by the concerted balance between lipid transport, synthesis, and degradation. Whereas scavenger receptor class B, type I (SR-B1) is critical for reverse cholesterol uptake by the liver, peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α and -β (PGC1α and PGC1β) are critical for lipid degradation and synthesis, respectively. Because betaine is a lipotropic agent, we have evaluated its effects on alcoholic steatosis. Betaine effectively prevented chronic alcohol-mediated (i) impaired SR-B1 glycosylation, plasma membrane localization, and consequent impaired cholesterol transport; and (ii) up regulation of PGC-1β, sterol regulatory element-binding protein 1c and downstream lipogenic genes with concomitant increased liver cholesterol, triglycerides and hepatic lipid score. Similarly, because of its anti-inflammatory and anti-fibrotic effects in other organs, we evaluated the protective effects of thymosin β4 (Tβ4) against carbon tetrachloride (CCl4)-induced hepatotoxicity in rat. Tβ4 prevented CCl4-induced (i) necrosis, inflammatory infiltration and up-regulation of α1(2)collagen, alpha-smooth muscle actin (α-SMA), platelet derived growth factor beta (PDGF-β) receptor and fibronectin mRNA expression; (ii) down-regulation of adipogenic gene, PPARγ and the up-regulation of epigenetic repressor gene, methyl CpG binding protein 2 (MeCP2) mRNA levels, suggesting that the anti-fibrogenic actions of Tβ4 involve the prevention of trans-differentiation of quiescent hepatic stellate cells into myo-fibroblasts largely by up-regulating PPARγ and by down-regulating MeCP2 genes. We therefore conclude that betaine and Tβ4 can effectively protect against alcoholic hepatosteatosis and hepatic fibrogenesis, respectively.
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA. raj.lakshman@va.gov.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA. raj.lakshman@va.gov.
authors.forename: M Raj
authors.initials: MR
authors.lastname: Lakshman
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Reyes-Gordillo
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Varatharajalu
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Arellanes-Robledo
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Leckey
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Mamatha
authors.initials: M
authors.lastname: Garige
authors.affiliation: Lipid Research Laboratory, VA Medical Center, 50 Irving Street, NW, Washington, DC, USA.|Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shah
keywords: Alcoholic liver injury; Betaine; Fatty liver; Fibrogenic genes; Fibrosis; Steatosis; Thymosin beta 4