Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

Abstract

Fatty liver or hepatic steatosis is a common health problem associated with abnormal liver function and increased susceptibility to ischemia/reperfusion injury. The objective of this study was to investigate the effect of the fatty acid synthase inhibitor cerulenin on hepatic function in steatotic ob/ob mice. Different dosages of cerulenin were administered intraperitoneally to ob/ob mice for 2 to 7 days. Body weight, serum AST/ALT, hepatic energy state, and gene expression patterns in ob/ob mice were examined. We found that cerulenin treatment markedly improved hepatic function in ob/ob mice. Serum AST/ALT levels were significantly decreased and hepatic ATP levels increased in treated obese mice compared to obese controls, accompanied by fat depletion in the hepatocyte. Expression of peroxisome proliferator-activated receptors α and γ and uncoupling protein 2 were suppressed with cerulenin treatment and paralleled changes in AST/ALT levels. Hepatic glutathione content were increased in some cases and apoptotic activity in the steatotic livers was minimally changed with cerulenin treatment. In conclusion, these results demonstrate that fatty acid synthase blockade constitutes a novel therapeutic strategy for altering hepatic steatosis at non-stressed states in obese livers.

CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease

“…It should be noted that CMS121 does show additional protection in glutamate and erastin-induced oxytosis/ferroptosis, but not in RSL3 induced lipid peroxidation. This is likely due to the fact that CMS121 maintains GSH levels under oxidative stress, in vitro [ 34 ], thereby preserving the substrate for the lipid peroxidation detoxifier GPX4, whereas FASN knockdown is not expected to affect GSH levels in the short term [ 63 ]. RSL3, on the other hand inhibits GPX4, inducing lipid peroxidation independently of the GSH levels.…”

Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

“…In western countries, about 30% of the general population suffers from hepatic steatosis, which has now become the most widespread cause of chronic liver disease. It has been realized that steatotic livers are more susceptible to injuries including IRI than healthy livers [ 3 ]. In the United States, liver transplantations account for approximately 23% of the total transplant surgeries [ 4 ], and many patients suffer from IRI.…”

Downregulation of fatty acid synthase complex suppresses cell migration by targeting phospho-AKT in bladder cancer

“…The natural product Cer is a mycotoxin which was initially developed as an anti-fungal agent and is now widely used as a natural inhibitor of FASN activity (17,18). Furthermore, transfection with siRNA is a commonly used method for silencing the expression of specific genes (19).…”