Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is the most severe and progressive form of nonalcoholic fatty liver disease (NAFLD), which can lead to life-threatening conditions, however, there is still no approved drug for the treatment of NASH. In this study we used human-like NASH mouse model and treated orally with isorhamnetin at a dose of 50 mg/kg to analyze the effect of isorhamnetin on the progression of NASH. NASH-induced mice represented severe steatosis with inflammation, and fibrosis in liver accompanied with high level of liver injury markers in serum. Isorhamnetin treatment reduced intrahepatic lipid accumulation and TG content by inhibiting de novo lipogenic pathway in NASH-induced mice. Consistent with this, isorhamnetin-treated NASH mice showed improved liver injury markers, reduced collagen deposition as well as decreased gene expression of fibrogenic markers. Taken together, here we showed for the first time that synthesized isorhamnetin alleviates pathologic features of NASH and thus can potentially contribute to NASH drug development.

Effects of Isorhamnetin in Human Amniotic Epithelial Stem Cells in vitro and Its Cardioprotective Effects in vivo

“…In the present study, we have evaluated the cardioprotective potential of ISO in hAESCs. Previously, we have reported that ISO, a flavonol, alleviates hepatic fibrosis in NASH model mice (Ganbold et al, 2019). Although several flavonols have been reported to improve cardiac dysfunction and fibrosis (Suzuki et al, 2007;Li et al, 2013;Geetha et al, 2014;Guo et al, 2015;Zhang et al, 2018), very little is known about the effect of ISO on cardiac hypertrophy and fibrosis.…”

“…It has anti-inflammatory, antioxidant, antiadipogenic, and antitumor activities (Hu et al, 2015;Yang et al, 2016). We have previously reported the anti-oxidant, antiobesity, and antifibrotic effects of ISO in rodent models (Zar Kalai et al, 2013;Ganbold et al, 2019). Ganbold et al (2019) reported that ISO could alleviate steatosis and fibrosis in a non-alcoholic steatohepatitis (NASH) mouse model by reducing the expression of liver injury marker transforming growth factor β (Tgf β), and the fibrogenic marker Collagen type I alpha 1 (Col1a1).…”

“…We have previously reported the anti-oxidant, antiobesity, and antifibrotic effects of ISO in rodent models (Zar Kalai et al, 2013;Ganbold et al, 2019). Ganbold et al (2019) reported that ISO could alleviate steatosis and fibrosis in a non-alcoholic steatohepatitis (NASH) mouse model by reducing the expression of liver injury marker transforming growth factor β (Tgf β), and the fibrogenic marker Collagen type I alpha 1 (Col1a1). However, little is known about the possible protective effect of ISO against cardiac fibrosis or hypertrophy (Gao et al, 2017).…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Although studies on the impact of luteolin in a more chronic model of liver fibrosis are desired, these data pointed towards therapeutic application of this drug in patients with hepatic fibrosis [97]. Similarly, in a study of Ganbold et al [3], it was recently shown that administration of isorhamnetin, another natural flavonoid to human-like NASH mice, resulted in improved steatosis, liver injury, and fibrosis, pointing towards its therapeutic potential in NASH.…”

“…If steatosis is not managed in time, resident liver cells (e.g., Kupffer and hepatic stellate cells) become activated and immune cells (mainly macrophages) infiltrate the liver, a condition defined as NASH. This progressive form of NAFLD [3] can further trigger hepatocyte damage with/without fibrosis and increase the risk of cirrhosis [4] and hepatocellular carcinoma (HCC) [5]. In contrast to alcoholic liver disease-and viral hepatitis-induced HCC, NASH-related HCC is currently the most rapid growing indication for liver transplant in HCC patients [6].…”