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

A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl4)-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 CCl4-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl4 + PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl4 injection to the end. As expected, PBA significantly attenuated CCl4-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl4-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl4-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, CCl4-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, CCl4-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl4-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl4-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (86 K)Download as PowerPoint slideHighlights► CCl4 induces hepatic ER stress, inflammation, HSC activation and hepatic fibrosis. ► PBA alleviates CCl4-induced hepatic ER stress and UPR signaling activation. ► PBA inhibits CCl4-induced hepatic NF-κB activation and ERK and JNK phosphorylation. ► PBA effectively protects against CCl4-induced HSC activation and hepatic fibrosis. ► ER stress is involved in CCl4-induced hepatic inflammation and fibrogenesis.