NCX 1000 Alone or in Combination with Vitamin E Reverses Experimental Nonalcoholic Steatohepatitis in the Rat Similarly to UDCA

Yara Haddad,Pierre S Haddad,Diane Vallerand,Jean Spénard,Antoine Brault

doi:10.4061/2011/136816

Yara Haddad, Pierre S Haddad + Show 3 more

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https://doi.org/10.4061/2011/136816

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Abstract

We explored the therapeutic effect of NCX 1000, a derivative of ursodeoxycholic acid (UDCA) with nitric oxide (NO) donating properties, alone or in combination with vitamin E, in an experimental model of NASH in the rat. Methods. A control group was fed a standard liquid diet (Control), and the NASH groups were fed a high-fat liquid diet for 12 weeks without (NASH) or with simultaneous daily gavage with either NCX 1000 at 15 or 30 mg/kg (N15 and N30, resp.), or N15 plus vitamin E 100 mg/kg (N15 + VitE) for the last 6 weeks; UDCA 17.2 mg/kg was used as a reference. Results. NASH rats developed all key features of the disease. Treatments with N30 improved liver histology, decreased lipid peroxidation, and completely suppressed increases in LDH release, plasma insulin, and TNF-α. It also decreased O2 ∙− release and returned liver weight and glutathione back to normal. All effects were similar to the reference treatment, UDCA. The N15 treatment was less efficient than the N30 group, but became comparable to the latter when combined to vitamin E. Conclusion. Our study demonstrates that NCX 1000 has potent cytoprotective, antioxidant, and hypoinsulinemic properties that can be enhanced by combination with vitamin E.

Highlights

Nonalcoholic steatohepatitis (NASH) was characterized for the first time by Ludwig and colleagues in 1980 [1] as the inflammatory stage following reversible steatosis in the liver
After 12 weeks of the NASH-inducing fat diet, there were no significant differences in body weight (BW) or weight gain (WG) between groups
The liver weight (LW) decreased significantly in the NCX 30 mg/kg (N30) group compared with the NASH group (P < 0.05), to the ursodeoxycholic acid (UDCA) group

Summary

Introduction

Nonalcoholic steatohepatitis (NASH) was characterized for the first time by Ludwig and colleagues in 1980 [1] as the inflammatory stage following reversible steatosis in the liver. It is part of the nonalcoholic fatty liver disease (NAFLD) spectrum, which is the most common cause of hepatic illness. The pathogenesis of NASH is not entirely elucidated, it is well established that it involves a multiple-hit process [6] This includes insulin resistance and oxidative stress and underlies the development of macrovesicular steatosis, necroinflammatory lesions, Mallory body formation, hepatocyte ballooning, and collagen deposition [7,8,9,10]. Several remedies were investigated for the treatment of NASH but an efficient therapy has yet to be developed

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Results

Conclusion