Ethanol Induces Transforming Growth Factor‐α Expression in Hepatocytes, Leading to Stimulation of Collagen Synthesis by Hepatic Stellate Cells

Kato, Junji; Sato, Yasuhiro; Inui, Noriaki; Nakano, Yoichiro; Takimoto, Rishu; Takada, Kohich; Kobune, Masayoshi; Kuroiwa, Ganji; Miyake, Sachie; Kohgo, Yutaka; Niitsu, Yoshiro

doi:10.1097/01.alc.0000078614.44983.97

Cited by 29 publications

(29 citation statements)

References 41 publications

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“…It was also shown recently that ethanol induces transforming growth factor (TGF)-α production in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells [48]. These results suggest that TGF-α derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver disease.…”

Section: Cytokines and Anticytokine Therapymentioning

confidence: 75%

New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments

Lieber¹

2004

Curr Gastroenterol Rep

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Activation of methionine to S-adenosylmethionine is depressed in alcoholics. Its repletion opposes alcoholic liver cirrhosis in baboons, decreases mortality in cirrhotic patients, and opposes oxidative stress resulting from cytochrome P4502E1 (CYP2E1) induction by alcohol, ketones, and fatty acids. Their excess causes alcoholic and nonalcoholic steatohepatitis. CYP2E1 is also induced in Kupffer cells, promoting their activation and release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. The TNF-alpha inhibitor pentoxifylline decreased mortality from alcoholic hepatitis. Polyenylphosphatidylcholine (PPC), an antioxidant phosphatidylcholine mixture extracted from soybeans, 50% of which consists of the highly bioavailable dilinoleoylphosphatidylcholine, restores phospholipids of the damaged membranes and reactivates their enzymes, including phosphatidylethanolamine methyltransferase, needed for phospholipid regeneration. In baboons, PPC prevented cirrhosis by stimulating collagenase and by opposing lipid peroxidation, which produces the fibrogenic hydroxynonenal. PPC was beneficial in patients with alcoholic hepatitis, and it opposed fibrosis in heavy drinkers and decreased aminotransferases in patients with hepatitis C. The antioxidant silymarin also successfully opposed alcoholic cirrhosis in baboons and in some but not all clinical trials; this effect also pertains to a-tocopherol. The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically.

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Section: Cytokines and Anticytokine Therapymentioning

confidence: 75%

New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments

Lieber¹

2004

Curr Gastroenterol Rep

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“…The ability of the antioxidants used in this study to decrease serum TGF-α concentrations is in agreement with the findings of Lee et al [13] who reported that hepatic stellate cell activation, a critical step in hepatic fibrogenesis, by TGF-α was blocked by antioxidants, such as d-α-tocopherol. In addition, Kato et al [11] suggested that ethanol-induced TGF-α may contribute to the development of hepatic fibrosis in alcoholic liver diseases. Moreover, Ito et al [9] reported that the antibiotic nitrofurazone induces hepatocyte proliferation with a pathway involving increase in TGF-α, and this increase was blocked by concomitant administration of N-acetylcysteine.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of curcumin, α-lipoic acid, and N-acetylcysteine against carbon tetrachloride-induced liver fibrosis in rats

et al. 2011

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Liver fibrosis is a major health problem that can lead to the development of liver cirrhosis and hepatocellular carcinoma. On the other hand, several antioxidants have been shown to possess protective effect against liver fibrosis. Therefore, in the present work, the effectiveness of curcumin, α-lipoic acid, and N-acetylcysteine in protecting against carbon tetrachloride (CCl(4))-induced liver fibrosis as well as the mechanism(s) implicated in this protective effect was studied. The antioxidants used in this study resulted in hepatoprotective effect as evident by substantial decreases in collagen deposition in histopathological examinations in addition to significant decrease in serum levels of alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transpeptidase, bilirubin, and transforming growth factor-alpha (TGF-α) as well as hepatic malondialdehyde concentration, with a concurrent increase in serum matrix metalloproteinase-13 (MMP-13) and hepatic reduced glutathione (GSH) levels as compared to CCl(4) fibrotic group. In conclusion, curcumin, α-lipoic acid, and N-acetylcysteine protect rats against CCl(4)-induced liver fibrosis most possibly through their antioxidant activities and their capacities to induce MMP-13 and to inhibit TGF-α levels.

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“…It was previously demonstrated that ethanol induces TGF-α expression in hepatocytes, leading to the stimulation of collagen synthesis by HSCs (22). Furthermore, toxic iron overload was shown to modulate HSCs proliferation and gene expression by rat hepatocytes (23).…”

Section: Discussionmentioning

confidence: 97%

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

Li¹,

Tu²,

Deng³

et al. 2013

Biomedical Reports

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Abstract. This study was conducted in order to investigate whether hepatitis B surface S protein (HBs) was able to directly or indirectly promote the proliferation and expression of collagen type I (Col I) and α-smooth muscle actin (α-SMA) in hepatic stellate cells (HSCs). The LX-2 human cell line and the HepG2 human hepatocellular carcinoma cell line were employed as HSCs and as hepatocytes, respectively. Recombinant HBs was added to the LX-2 cells for 48 h and the cell proliferation was assessed by the MTT assay. Col I and α-SMA were measured in the supernatant by ELISA, following treatment of the LX-2 and̸or HepG2 cells with recombinant HBs. Transforming growth factor-β1 (TGF-β1) was also determined by ELISA in the HepG2 cell supernatants. The data demonstrated that high concentrations of recombinant HBs (10-50 ng/ml) inhibited the proliferation of LX-2 cells, whereas low concentrations (0.5-5 ng/ml) did not affect LX-2 cell proliferation. After treating LX-2 cells alone with recombinant HBs for 48 h, there was no significant increase in the Col I and α-SMA levels. However, Col I was increased ~1.7-fold in co-cultured (LX-2 and HepG2) cell supernatants following treatment with HBs for 24 h (HBs vs. control group: 48.51±3.51 vs. 28.23±2.55 ng̸ml, respectively). Furthermore, TGF-β1 was significantly increased in the HepG2 cell supernatants following treatment with recombinant HBs. Therefore, we concluded that HBs directly affected the proliferation of HSCs, but promoted the Col I expression in HSCs possibly by virtue of hepatocytes secreting TGF-β1. This may provide a novel explanation of the fibrogenetic mechanism induced by hepatitis B virus-related proteins. IntroductionThe infection with hepatitis B virus (HBV) is a major health concern worldwide. It is estimated that ~350 million individuals are carriers of the hepatitis B surface S protein (HBs) and over one million patients eventually succumb to HBV-related chronic liver diseases annually (1-2). Persistent HBV infection confers a high risk of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) (3). Three forms of viral particles may be detected in the serum of HBV-infected patients: 42-nm diameter mature virion particles, 22-nm diameter spherical particles and 22-nm diameter filamentous particles (4-5). Subviral particles (22 nm), composed of HBs, are unique in that do not contain viral DNA and usually exceed the numbers of virions by ≥1,000-fold in the patient serum (5). A number of individuals reportedly reached a state of non-replicative infection following persistent anti-virus therapy; however, numerous HBs particles were still detected in their serum and the prolonged immunological response to infection may result in the development of fibrosis in the majority of the patients and eventually lead to the development of cirrhosis, liver failure, or HCC in ~40% of the patients (6). During this process, HBs may play an important role. However, the mechanism underlying the hepatic fibrogenesis induced by HBs has not yet been fully eluci...

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Ethanol Induces Transforming Growth Factor‐α Expression in Hepatocytes, Leading to Stimulation of Collagen Synthesis by Hepatic Stellate Cells

Abstract: These results suggest that TGF-alpha derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver diseases.

Cited by 29 publications

References 41 publications

New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments

New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments

Protective effects of curcumin, α-lipoic acid, and N-acetylcysteine against carbon tetrachloride-induced liver fibrosis in rats

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

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