Abstract
Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4+ and CD8+ T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH.
Highlights
Randomized controlled trial performed to date, the PIVENS trial demonstrated that vitamin E reduced hepatic steatosis and lobular inflammation in adult patients with NASH7
This study compared the effects of the potent antioxidant carotenoid astaxanthin and vitamin E on NASH and elucidated the potential mechanism underlying the effects
The different mechanisms of action determined by comparing astaxanthin and vitamin E in NASH mice are intriguing because both of these lipophilic antioxidants suppress hepatic lipid peroxidation to an equivalent extent (Fig. 2d)
Summary
Randomized controlled trial performed to date, the PIVENS trial demonstrated that vitamin E reduced hepatic steatosis and lobular inflammation in adult patients with NASH7. There is a continuing need for additional and more effective therapies for patients with NASH. Micronutrient antioxidants, such as vitamins and carotenoids, are depleted severely in the serum and liver tissue of patients with chronic liver diseases and cirrhosis[8,9]. Carotenoids inhibit lipid peroxidation as potently as does vitamin E12,13, but carotenoid supplementation has not been used widely as an antioxidant therapy for the treatment of NASH. We have shown that β -cryptoxanthin, an antioxidant carotenoid, inhibits the progression of NASH in mice[14,15]. We hypothesized that the administration of astaxanthin would inhibit the progression of NASH by suppressing lipotoxicity-induced oxidative stress and the subsequent lipid peroxidation and insulin resistance.
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