Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice

Journal Article · Tue Jan 15 04:00:00 EST 2013 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.11.007· OSTI ID:22216044

Wang, Jian-Qing ^[1]; Chen, Xi ^[2]; Zhang, Cheng ^[3]; Tao, Li ^[2]; Zhang, Zhi-Hui; Liu, Xiao-Qian ^[3]; Xu, Yuan-Bao ^[3]; Wang, Hua ^[3]; Li, Jun ^[1]; Xu, De-Xiang ^[3]

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1. School of Pharmacy, Anhui Medical University, Hefei, 230032 (China)
2. First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China)
3. Department of Toxicology, Anhui Medical University, Hefei, 230032 (China)

A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl{sub 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{sub 4}-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl{sub 4} (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl{sub 4} + PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl{sub 4} injection to the end. As expected, PBA significantly attenuated CCl{sub 4}-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl{sub 4}-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl{sub 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{sub 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{sub 4}-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl{sub 4}-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl{sub 4}-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation. Highlights: ► CCl{sub 4} induces hepatic ER stress, inflammation, HSC activation and hepatic fibrosis. ► PBA alleviates CCl{sub 4}-induced hepatic ER stress and UPR signaling activation. ► PBA inhibits CCl{sub 4}-induced hepatic NF-κB activation and ERK and JNK phosphorylation. ► PBA effectively protects against CCl{sub 4}-induced HSC activation and hepatic fibrosis. ► ER stress is involved in CCl{sub 4}-induced hepatic inflammation and fibrogenesis.

• OSTI ID: 22216044
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 266; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTIN
CARBON TETRACHLORIDE
COLLAGEN
ENDOPLASMIC RETICULUM
FIBROSIS
GLUCOSE
GROWTH FACTORS
INFLAMMATION
INOSITOL
LIVER
MICE
MUSCLES
PATHOGENESIS
PHOSPHORYLATION
RNA
TRANSCRIPTION FACTORS
TRANSLOCATION