title: 4-Phenylbutyric acid regulates CCl4-induced acute hepatic dyslipidemia in a mouse model: A mechanism-based PK/PD study.
abstract: Endoplasmic reticulum (ER) stress and associated protein aggregation are closely associated with human diseases, including alterations in hepatic lipid metabolism. Inhibition of ER stress can have a significant effect on the prevention of hepatic dyslipidemia. Here, we studied the role of 4-phenylbutyric acid (4-PBA), a chemical chaperone, on ER stress-induced hepatic lipid accumulation. We studied ER stress induction following CCl4 exposure and delineated mechanisms of the CCl4-induced ER stress response in liver tissue from mice. CCl4 affected the formation of disulfide bonds through excessive hyper-oxidation of protein disulfide isomerase (PDI). Increased complex formation between PDI and its client proteins persisted in CCl4-exposed samples. Conversely, 4-PBA inhibited ER stress via secretion of apolipoprotein B and prevention of hepatic lipid accumulation. We also studied the mechanism-based pharmacokinetic and pharmacodynamic profiles and identified the ER stress-related proteins GRP78 and CHOP, along with plasma apolipoprotein B and triglyceride levels, as novel biomarkers of ER stress-induced hepatic lipid accumulation. ER stress and its clinical relevance for therapeutic approaches were well correlated with the activity of the ER stress regulator 4-PBA, which may be a promising drug candidate for the treatment of hepatic lipid accumulation, such as hepatic steatosis.
authors.affiliation: Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea.
authors.forename: Anu
authors.initials: A
authors.lastname: Marahatta
authors.affiliation: Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea.
authors.forename: Bidur
authors.initials: B
authors.lastname: Bhandary
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan 570-749, South Korea.
authors.forename: Hyung-Ryong
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea. Electronic address: hjchae@jbnu.ac.kr.
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry; D050171:Dyslipidemias / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D017510:Protein Folding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D004220:Disulfides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010654:Phenylbutyrates; D017382:Reactive Oxygen Species; C075773:4-phenylbutyric acid; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1
keywords: 4-Phenylbutylamine (PubChem CID: 83242); Apolipoprotein B; Carbon tetrachloride (PubChem CID: 5943); ER stress; Pharmacodynamics; Phenylbutyric acid; Protein disulfide Isomerase; Tunicamycin (PubChem CID: 16760689)