Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice #

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. The hyperinsulinemia that occurs as a consequence of insulin resistance is thought to be an important contributor to the development of fatty liver. We have shown that the iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. The present study was designed to assess the impact of AMP-DNM on insulin levels, liver triglyceride synthesis, and gene expression profile. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose values to levels found in lean mice, and decreased insulin concentration. The expression of sterol regulatory element-binding protein 1c target genes involved in fatty acid synthesis normalized. AMP-DNM treatment significantly reduced liver to body weight ratio and reversed hepatic steatosis, comprising fat as well as inflammatory markers. In addition, AMP-DNM treatment corrected to a large extent the gene expression profile of ob/ob mice livers toward the profile of lean mice. Conclusion: Pharmacological lowering of glycosphingolipids with the iminosugar AMP-DNM is a promising approach to restore insulin signaling and improve glucose homeostasis as well as hepatic steatosis.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Clinically, treatment led to decreased plasma cholesterol and triglyceride levels. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose levels, and decreased insulin concentrations (21,22,167). The result was related with the normalization of the expression of SREBP1c target genes involved in fatty acid synthesis.…”

“…The liver/body weight ratio decreases with the reversal of hepatic steatosis and with an increase in inflammatory markers. AMP-DNM treatment corrected the gene expression profile of ob/ob mouse livers (21,22,167). A reduction of GSL biosynthesis in the adipose tissue of ob/ob mice restored insulin signaling in isolated ex vivo insulinstimulated adipocytes (168,172,176).…”

“…In ob/ob mice, HFD mice, and ZDF rats, AMP-DNM normalized the elevated tissue of GC and GM3 levels, subsequently lowering the circulating glucose level, hence improving oral glucose tolerance and insulin sensitivity in muscle and liver (5,6,161). AMP-DNM resulted in a 70% reduction of GSLs in the liver hepatoma cell line HepG2 (20,21,165). The effect was associated with a significant up-or downregulation of target genes for the transcription factors SREBP1 or SREBP2, which activate genes in the sterol biosynthesis pathway.…”

“…Obesity-related inflammatory pathways modulate SL metabolism (20,23,24). Metabolomics profiling, liquid chromatography mass spectrometry, and gene expression analyses showed increased hepatic Cer and a higher levels of SLs in NASH (21,22,28,30,36,38). The metabolism of SL is dysregulated in obesity, in which increased adipose tissue mass affects whole body insulin resistance and cardiovascular disease risk via adipose-tissue derived inflammatory cytokines that induce chronic inflammation, as well as increasing cardiovascular risk while the antagonizing insulin signaling and mitochondrial function, thereby impairing glucose homeostasis (23,149,153).…”

“…The effect was associated with a significant up-or downregulation of target genes for the transcription factors SREBP1 or SREBP2, which activate genes in the sterol biosynthesis pathway. The associated increase in cholesterol production was as a result of the activation of the cholesterol biosynthesis pathway (20,21,165). AMP-DNM treatment decreased plasma level of triglycerides and cholesterol, while neutral sterol, biliary lipids, and bile flow excretion is increased twofold (22,23,166).…”