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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver disease, affecting approximately 25% of the global population [1]
These findings suggest that the infiltration of monocytes-derived macrophages mediates the progression of non-alcoholic steatohepatitis (NASH) and ASTN treatment can modulate the intrahepatic immune response to inhibit NASH development
A CDAHFD was selected to induce mouse NASH to investigate the role of ASTN in NASH progression
Summary
Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver disease, affecting approximately 25% of the global population [1]. The histological manifestations of NAFLD range from simple liver steatosis to aggressive non-alcoholic steatohepatitis (NASH) characterized by ballooning hepatocyte injury, lobular and/or portal inflammation associated with or without liver fibrosis [2]. NAFLD-associated metabolic comorbidities include obesity, type 2 diabetes (T2D), hypertension, and hyperlipidemia, and metabolic syndrome [3]. NAFLD and its comorbidities are often associated with severe diseases, such as chronic kidney disease [4] and hospitalized cardiovascular disease [5]. Many anti-obesity and anti-diabetic drugs are under investigation, no agent is approved yet for NAFLD treatment [7].
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