title: Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice.
abstract: A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl(4))-induced hepatic fibrosis. Phenylbutyric acid (PBA) is a well-known chemical chaperone that inhibits endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling. In the present study, we investigated the effects of PBA on CCl(4)-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl(4) (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl(4)+PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl(4) injection to the end. As expected, PBA significantly attenuated CCl(4)-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl(4)-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl(4)-induced hepatic nuclear factor kappa B (NF-κB) p65 translocation and extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) phosphorylation. Interestingly, CCl(4)-induced α-smooth muscle actin (α-SMA), a marker for the initiation phase of HSC activation, was significantly attenuated in mice pretreated with PBA. Correspondingly, CCl(4)-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl(4)-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl(4)-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation.
authors.affiliation: School of Pharmacy, Anhui Medical University, and Second Affiliated Hospital, Hefei, China.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Liu
authors.forename: Yuan-Bao
authors.initials: YB
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D010654:Phenylbutyrates; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C075773:4-phenylbutyric acid; D002251:Carbon Tetrachloride