Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #

Abstract

Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in dietinduced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis. Conclusion: These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH. (HEPATOLOGY 2009;50:85-93.)

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

“…These effects were linked with increased intrahepatic trapping of CD8ϩ T and NKT lymphocytes (186,192,196). A similar beneficial effect of a combination of GC and LC was noted in the Psammomys obesus high-energy diet model, and its treatment was associated with decreased liver enzymes, liver weight, hepatic fat, and improved liver histology, with improved serum cholesterol and triglyceride levels (185,191,195). Preliminary results support their beneficial role in patients with NASH (189,193).…”

“…GENZ-123346 is a specific inhibitor of GCS, an enzyme that catalyzes an important step in the conversion of Cer to GSLs. Genz-123346 alleviates insulin resistance, reversing hyperinsulinemia and improving glucose tolerance in mice with diet-induced insulin resistance and NASH in animal models (185,186,163,164,189,190).…”

“…FXR activation attenuates LPSinduced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages (181,185,190). In a recent clinical trial, obeticholic acid improves the histological features of NASH (126,130,191).…”

Glucosylceramide synthase in the fat body controls energy metabolism in Drosophila

“…Recent drug and in vitro studies have suggested that suppression of GlcT-1 function may present a novel strategy for treating diseases such as obesity (9)(10)(11). In Drosophila and mammals, GlcT-1 function and p38-ATF2 signaling are conserved.…”

Ceramides as modulators of cellular and whole-body metabolism

“…Aerts et al found that a GCS inhibitor improved hepatic insulin sensitivity (112) and prolonged treatment reduced hepatic inflammation with diet-induced obesity (113); similar improvements have been observed with a second GCS inhibitor (114). These compounds appear to reverse many of the complications associated with obesity, including diabetes (112), adipose inflammation (113), hepatic steatosis (115), and atherosclerosis (114), though reports on the latter are controversial (116). GM3 ganglioside, a higher order glycosphingolipid, may be the primary antagonist of insulin action.…”