Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity

Abstract

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-β1, and IL-1β. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.

Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options

“…We and other researchers show that natural anti-oxidative and anti-inflammatory product astaxanthin can modulate intrahepatic and systemic inflammation and oxidative stress to inhibit NASH and liver fibrosis ( 120 ). Molecular mechanism study showed that metformin treatment inhibited the expression of IL-12-mediated proliferation, migration, and invasion of HCC cells and attenuated ectopic IL-22 expression-caused HCC progression by activating the Hippo signaling pathway ( 121 ).…”

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

“…For example, the frequency of macrophages was increased in the NASH liver in amylin liver NASH (AMLN) diet-fed mice compared to that in standard chow diet-fed mice [ 15 ]. Our research study also showed that monocyte-derived macrophages increased in the liver of wild-type mice fed a choline-deficient, L-amino acid-defined, high-fat diet [ 16 ]. Other than that, adaptive immunity, including T cells such as the ratio of T helper (Th) cells/T regulatory cells (Tregs) and B cells, are activated or altered in the development of NAFLD [ 17 , 18 ].…”

“…Activation of HSCs, the major cells that contribute to liver fibrosis, is mediated by the activation of intrahepatic immunity during NASH. For example, proinflammatory cytokines such as TNF-α, transforming growth factor (TGF)-β1, and IL-1β expressed by intrahepatic macrophages can activate HSCs to promote the progression of liver fibrosis and NASH [ 16 ]. In contrast, a recent study showed that tissue-resident memory CD8 + T cells can trigger apoptosis of activated HSCs via Fas (TNF receptor superfamily, member 6)/FasL-mediated signaling [ 75 ].…”

Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

“…This is a unique feature that other models do not have, and it simulates some of the characteristics of human NAFLD. The CDAHFD model has significant applications in studying the role of novel therapeutic targets (such as TSP-1, transient receptor potential canonical (TRPC) 77 , 78 , traditional Chinese medicine (such as nobiletin, astaxanthin) 79 , 80 or western medicine (such as metformin and PPAR agonist) in NAFLD/NASH development 74 , 81 .…”