By Timothy J. King, Ph.D., Vice President, Research
The role of oxidative stress and inflammation in liver injury and liver dysfunction as well as the potential for antioxidants to ameliorate liver disease has been established in both animal models and human trials [Sanchez-Valle et al. 2012; Pacana and Sanyal 2012]. Studies utilizing rodent models of liver disease have also demonstrated the efficacy of astaxanthin (ASTX) in ameliorating liver injury [Kang et al. 2001; Curek et al. 2010]. Earlier this year, Shen et al. extended these observations by publishing the effects of ASTX treatment in mouse models of surgically induced (bile duct ligation) and chemically induced (carbon tetrachloride) liver injury [Shen et al. 2014]. In both models, Shen et al. observed that ASTX: 1) significantly reduced, pathologically elevated liver enzyme levels (ALT and AST), 2) significantly decreased histological hepatocytic necrosis, liver lobule damage and pericellular bridging fibrosis, and 3) attenuated liver fibrosis.
Now, in an animal model more reflective of the environment-induced hepatic dysfunction seen in human clinical settings, Yang et al. further support these previously published studies by utilizing a mouse model of high-fat diet-induced hepatic stress. Yang et al. fed C57BL/6j mice (N=8/group) a high fat diet (35% w/w) with or without ASTX (0.003%, 0.01%, 0.03%) for 12 weeks. Mice supplemented with 0.03% ASTX exhibited significantly decreased plasma triacylglcerides (TAG) supporting a hypotriacylglycerolaemic effect of ASTX. Hepatic TAGs were also reduced ~30% but was not statistically significant. Several published studies have likewise shown the capacity of ASTX to reduce triglyceride levels in animal models of metabolic dysfunction [Yang et al. 2011; Ryu et al. 2012; Bhuvaneswari et al. 2010].
Importantly, the Yang et al. study supports Shen et al. observations demonstrating the capacity of ASTX to attenuate pathologically elevated liver enzyme levels. In Yang et al., ASTX treated mice (0.03%) exhibited significantly reduced aspartate transaminase liver enzyme levels (AST=-~45% p<0.05). Alanine transaminase levels (ALT) were also reduced ~60%, albeit not significantly, most likely due to the dramatic inter-individual ALT level variation common to this species.
To evaluate ASTX influence on gene expression, Yang et al. compared gene transcription profiles in liver from both control and ASTX treated groups. ASTX significantly increased expression of acyl-CoA oxidase 1 (ACOX-1), a rate-limiting enzyme in peroxisomal fatty acid beta-oxidation. In contrast, ASTX also increased two genes involved in lipogenesis: fatty acid synthase and diglyceride acyltransferase 2. As reported previously using cell culture system studies [Li et al. 2013; Saw et al. 2013], Yang et al. observed increased expression of the antioxidant defense system nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream target genes superoxide dismutase-1 (SOD1) and glutathione peroxidase 1 (GP-1).
In addition, the anti-inflammatory influence of ASTX was evaluated using extracted splenocytes challenged with the pro-inflammatory agent, lipopolysaccharide (LPS). Decreased interleukin-6 (IL-6) expression levels in splenocytes extracted from ASTX-treated mice underscore the established anti-inflammatory properties of ASTX. Similar observations of in vivo ASTX-induced decreases in IL-6 have been published previously [Arunkumar et al. 2011; Chan et al. 2012; Izumi-Nagai et al. 2008].
In summary, these results support the potential role of ASTX in reducing liver stress by decreasing pathologically elevated liver enzymes (AST, ALT), decreasing circulating and hepatic triglyceride levels, influencing lipogenic/lipid metabolic gene expression patterns, and attenuating inflammatory pathways. This newly published data joins many previously published studies in underscoring the potential for ASTX to ameliorate liver-associated oxidative stress, inflammation and the resulting pathology of liver disease in addition to aspects of dyslipidemia (hypertriglyceridemia).
Yang Y, Pham TX, Wegner CJ, Kim B, Ku CS, Park YK, Lee JY, 2014.
Astaxanthin lowers plasma TAG concentrations and increases hepatic antioxidant gene expression in diet-induced obesity mice.
British Journal of Nutrition, E-published October 20:1-8.
Sánchez-Valle V, Chávez-Tapia NC, Uribe M, Méndez-Sánchez N, 2012.
Role of oxidative stress and molecular changes in liver fibrosis: a review.
Current Medicinal Chemistry, 19(28):4850-4860.
Pacana T, Sanyal AJ, 2012.
Vitamin E and nonalcoholic fatty liver disease.
Current Opinion in Clinical Nutritional and Metabolic Care, 15(6):641-648.
Kang JO, Kim SJ, Kim H, 2001.
Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats.
Methods and Findings in Experimental and Clinical Pharmacology, 23(2):79-84.
Curek GD, Cort A, Yucel G, Demir N, Ozturk S, Elpek GO, Savas B, Aslan M, 2010.
Effect of astaxanthin on hepatocellular injury following ischemia/reperfusion.
Shen M, Chen K, Lu J, Cheng P, Xu L, Dai W, Wang F, He L, Zhang Y, Chengfen W, Li J, Yang J, Zhu R, Zhang H, Zheng Y, Zhou Y, Guo C, 2014.
Protective effect of astaxanthin on liver fibrosis through modulation of TGF-β1 expression and autophagy.
Mediators of Inflammation, 2014:1-14.
Yang Y, Seo JM, Nguyen A, Pham TX, Park HJ, Park Y, Kim B, Bruno RS, Lee J, 2011.
Astaxanthin-rich extract from the green alga Haematococcus pluvialis lowers plasma lipid concentrations and enhances antioxidant defense in apolipoprotein E knockout mice.
Journal of Nutrition, 141(9):1611-1617
Ryu SK, King TJ, Fujioka K, Pattison J, Pashkow FJ, Tsimikas S, 2012.
Effect of an oral astaxanthin prodrug (CDX-085) on lipoprotein levels and progression of atherosclerosis in LDLR(-/-) and ApoE(-/-) mice.
Bhuvaneswari S, Arunkumar E, Viswanathan P, Anuradha CV, 2010.
Astaxanthin restricts weight gain, promotes insulin sensitivity and curtails fatty liver disease in mice fed a obesity-promoting diet.
Process Biochemistry, 45(8):1406-1414.
Li Z, Dong X, Liu H, Chen X, Shi H, Fan Y, Hou D, Zhang X, 2013.
Astaxanthin protects ARPE-19 cells from oxidative stress via upregulation of Nrf2-regulated phase II enzymes through activation of PI3K/Akt.
Molecular Vision, 19:1656-1666.
Saw CL, Yang AY, Guo Y, Kong AN, 2013.
Astaxanthin and omega-3 fatty acids individually and in combination protect against oxidative stress via the Nrf2-ARE pathway.
Food and Chemical Toxicology, 62:869-875.
Arunkumar E, Bhuvaneswari S, Anuradha CV, 2012.
An intervention study in obese mice with astaxanthin, a marine carotenoid–effects on insulin signaling and pro-inflammatory cytokines.
Food & Function, 3(2):120-126.
Chan KC, Pen PJ, Yin MC, 2012.
Anticoagulatory and antiinflammatory effects of astaxanthin in diabetic rats.
Journal of Food Science, 77(2):H76-H80.
Izumi-Nagai K, Nagai N, Ohgami K, Satofuka S, Ozawa Y, Tsubota K, Ohno S, Oike Y, Ishida S, 2008.
Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin.
Investigative Ophthalmology & Visual Science, 49(4):1679-1685.