S-Adenosyl-L-Methionine Attenuates Oxidative Stress and Hepatic Stellate Cell Activation in an Ethanol-LPS-Induced Fibrotic Rat Model

Abstract

Previous studies report S-adenosyl-L-methionine (SAMe) can exert hepatoprotective effects. At present, the role of SAMe in affecting the activation and/or proliferation of hepatic stellate cells (HSCs) during alcohol-induced fibrotic disease progression is poorly understood. In the human disease state, chronic ethanol intake increases hepatic exposure to LPS and magnifies the hepatic insult leading to fibrosis and cirrhosis. In this study, we developed a "2-hit" ethanol-LPS fibrotic liver rat model with which to investigate the effects of SAMe as a hepatic antifibrotic treatment. Male rats were maintained on liquid diets containing either ethanol or isocalorically matched controls for 8 weeks. Animals received ethanol alone (E), ethanol concomitant with twice weekly LPS injections (EL), or ethanol, LPS, and daily SAMe injections. When using this model, SAMe-treated animals demonstrated significantly decreased fibrosis, oxidative stress, steatosis, and improved liver function versus the EL group. In addition, the EL group showed increased HSC activation, an effect that was abrogated by the addition of SAMe. Analysis of the transforming growth factor-beta (TGF-beta) signaling pathways demonstrated increased hepatic TGF-beta and Smad3 messenger RNA expression in the E and EL groups, which was inhibited in the presence of SAMe. Conversely, SAMe led to increased Smad7 (an inhibitor of TGF-beta signaling) messenger RNA expression. These data demonstrate chronic ethanol feeding combined with LPS induces liver fibrosis, and the addition of SAMe significantly reduces hepatic injury and fibrosis through inhibition of oxidative stress and HSC activation.

The proanthocyanidins inhibit dimethylnitrosamine-induced liver damage in rats

“…Much experimental and clinical data indicate that a common link between chronic liver damage and hepatic fibrosis may be related to oxidative stress (Vendemiale et al, 2001;Bruck et al, 2007;Karaa et al, 2008), which has been reported to be associated with the HSC activation (Friedman, 2008b). There is sufficient evidence suggesting that lipid peroxidation can occur in both acute and chronic liver injuries (Chen et al, 2001).…”

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…Several investigations indicated that the threshold for hepatotoxicity from many xenobiotics was lowered by co-exposure to LPS. 22,23,[40][41][42][43] The ability of LPS to stimulate an inflammatory response may account for its pathogenicity in the liver. LPS is a potent activator of liver tissue macrophages (Kupffer cells) through toll-like receptors (TLRs) (Figure 6).…”

Alcohol metabolites and lipopolysaccharide: Roles in the development and/or progression of alcoholic liver disease

“…Karaa et al [66] examined how SAMe acted as an antifibrotic agent by looking at liver fibrosis, HSC activation, and collagen deposition. This model used Lieber DiCarli liquid diet containing ethanol (or a calorie matched diet) concurrently with twice weekly LPS injections during an eight week period.…”

“…These events increase gut permeability allowing for more LPS release making LPS clearance more difficult [10,11,19] . Karaa et al [66] looked for therapeutic agents that slow or possibly prevent ALD progression. S-adenosyl-L-methionine (SAMe) has previously been shown to be a precursor in glutathione (GSH) synthesis in the transsulferation pathway, which is an important hepatic antioxidant.…”