Abstract
The hepatic adiponectin and farnesoid X receptor (FXR) signaling pathways play multiple roles in modulating lipid and glucose metabolism, reducing hepatic inflammation and fibrosis, and altering various metabolic targets for the management of non-alcoholic fatty liver disease (NAFLD). Alisma orientale (AO, Ze xie in Chinese and Taeksa in Korean) is an herbal plant whose tubers are enriched with triterpenoids, which have been reported to exhibit various bioactive properties associated with NAFLD. Here, the present study provides a preclinical evaluation of the biological functions and related signaling pathways of AO extract for the treatment of NAFLD in a Western diet (WD)-induced mouse model. The findings showed that AO extract significantly reversed serum markers (liver function, lipid profile, and glucose) and improved histological features in the liver sections of mice fed WD for 52 weeks. In addition, it also reduced hepatic expression of fibrogenic markers in liver tissue and decreased the extent of collagen-positive areas, as well as inhibited F4/80 macrophage aggregation and inflammatory cytokine secretion. The activation of adiponectin and FXR expression in hepatic tissue may be a major mechanistic signaling cascade supporting the promising role of AO in NAFLD pharmacotherapy. Collectively, our results demonstrated that AO extract improves non-alcoholic steatohepatitis (NASH) resolution, particularly with respect to NASH-related fibrosis, along with the regulation of liver enzymes, postprandial hyperglycemia, hyperlipidemia, and weight loss, probably through the modulation of the hepatic adiponectin and FXR pathways.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is an umbrella term frequently mentioned to cover a group of hepatic manifestations of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and NASH-related fibrosis [1]
A sustained weight reduction of 10% or more was observed in mice fed Western diet (WD) plus 250 mg/kg of Alisma orientale (Sam.) Juz. (AO) extract from week 42 to week 52, and the intervention of AO extract (250 mg/kg) led to a significant decrease in the amount of body weight gain at week 52 compared to WD-induced mice (Figure 2c, p < 0.05, compared to the WD group)
Mice exposed to WD diet for 52 weeks developed enlarged, heavy, and yellowish livers, representing higher hepatocyte lipid accumulation, but this distinguishable fatty infiltration and hepatomegaly were not found after AO extract treatment (Figure 2f)
Summary
Non-alcoholic fatty liver disease (NAFLD) is an umbrella term frequently mentioned to cover a group of hepatic manifestations of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and NASH-related fibrosis [1]. Using the International Classification of Diseases, tenth revision (ICD-10) published by the World Health Organization (WHO) in 2019, three codes of K76.0 (Fatty (change of) liver, not elsewhere classified), K75.8 (other specified inflammatory liver diseases (NASH), and K74 (Fibrosis and cirrhosis of liver) may be commonly selected by clinicians to fill in the electronic medical records of NAFLD patients [2]. As the number of patients diagnosed with NAFLD increases, so does the risk of mortality. A cohort study in Sweden reported that reversing all stages of biopsy-proven NAFLD lowers the risk of overall mortality and extrahepatic cancer [3]. Effective therapeutic strategies targeting various phenotypes of NAFLD, from simple steatosis to more serious forms of NASH and cirrhosis, are required to reduce the disease burden
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