Andrographolide ameliorates hepatic steatosis by suppressing FATP2-mediated fatty acid uptake in mice with nonalcoholic fatty liver disease

Abstract

Excessive intrahepatocellular lipid accumulation or steatosis is caused by abnormal lipid metabolism and a common character of nonalcoholic fatty liver disease (NAFLD), which may progress into cirrhosis and hepatocellular cancer. Andrographolide (Andro) is the primary active ingredient extracted from Andrographis paniculata, showing a protective role against dietary steatosis with the mechanism not fully understood. In this study, we showed that administration of Andro (50, 100, and 200 mg/kg/day for 8 weeks, respectively) attenuated obesity and metabolic syndrome in high-fat diet (HFD)-fed mice with improved glucose tolerance, insulin sensitivity, and reduced hyperinsulinemia, hyperglycemia, and hyperlipidemia. HFD-fed mice presented hepatic steatosis, which was significantly prevented by Andro. In vitro, Andro decreased the intracellular lipid droplets in oleic acid-treated LO2 cells. The selected RT-PCR array revealed a robust expression suppression of the fatty acid transport proteins (FATPs) by Andro treatment. Most importantly, we found that Andro consistently reduced the expression of FATP2 in both the oleic acid-treated LO2 cells and liver tissues of HFD-fed mice. Overexpression of FATP2 abolished the lipid-lowering effect of Andro in oleic acid-treated LO2 cells. Andro treatment also reduced the fatty acid uptake in oleic acid-treated LO2 cells, which was blunted by FATP2 overexpression. Collectively, our findings reveal a novel mechanism underlying the anti-steatosis effect of Andro by suppressing FATP2-mediated fatty acid uptake, suggesting the potential therapeutic application of Andro in the treatment of NAFLD. Graphical abstract

Transcriptomic analysis reveals pharmacological mechanisms mediating efficacy of Yangyinghuoxue Decoction in CCl4-induced hepatic fibrosis in rats

“…As a major organ for aliphatic acid synthesis and metabolism, the liver has the ability to synthesize, break down, and metabolize aliphatic acids ( Heeren and Scheja, 2021 ). In certain pathological states, such as obesity, hyperlipidemia, and hepatic fibrosis, the liver is susceptible to excessive lipid accretion ( Ran et al, 2023 ). Adipocyte proliferation, white blood cell infiltration, and cytokine release can induce the deposition and accretion of lipids in hepatocytes, exacerbating the occurrence and progression of hepatic fibrosis ( Suganami et al, 2012 ; van der Windt et al, 2018 ; Heeren and Scheja, 2021 ).…”

Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction

“…Hepatic expression of the FATP can significantly increase during the pathogenesis of NAFLD. Overexpression of FATP1, FATP2, and FATP3 has been confirmed at the hepatic mRNA level in a high-fat diet (HFD)-fed mouse model [40]. CD36 is another well-known FFA transporter overexpressed in NAFLD.…”

Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches

“…As well as carrying out its function as a fatty acid transporter, FATP5 can also activates long-chain fatty acids (LCFAs) through covalent coenzyme A attachment [ 56 ]. It has been reported that deletion or silencing of FATP5 reduces triglyceride levels in the liver and ameliorates diet-induced steatosis in rats [ 57 ]. The FATP5 variant rs56225452 gain-of-function was found to be associated with an increased risk of hepatic steatosis, elevated ALT levels, and enlarged insulin resistance [ 58 ].…”