Related Experiment Video
Updated: Jun 23, 2026
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice
Hongmei Zhao1, Malgorzata Przybylska, I-Huan Wu
1Genzyme Corp., Framingham, MA 01701-9322, USA.
Unlabelled:
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 diet-induced 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.
Insights
Inhibiting glycosphingolipid (GSL) synthesis improved glucose control and reduced fatty liver disease in obese mice. This approach may offer a new treatment for nonalcoholic steatohepatitis (NASH).
Area of Science:
- Biochemistry
- Metabolic Diseases
- Hepatology
Background:
- Hepatic steatosis is common in obesity and type 2 diabetes, preceding serious liver conditions like NASH.
- Previous studies suggest inhibiting glycosphingolipid (GSL) synthesis improves insulin sensitivity and glucose levels in diabetic models.
Purpose of the Study:
- To investigate the effects of inhibiting GSL synthesis on hepatic steatosis and glucose homeostasis in obese mouse models.
- To evaluate the therapeutic potential of targeting GSL synthesis for fatty liver disease.
Main Methods:
- Ob/ob mice and diet-induced obese mice were treated with a glucosylceramide synthase inhibitor for 7 weeks.
- Evaluated changes in glucose levels, HbA1c, liver/body weight ratio, liver triglycerides, and gene expression.
- Assessed liver pathology and glucosylceramide (GL1) levels.
Main Results:
- Inhibiting GSL synthesis improved glucose homeostasis and markedly reduced hepatic steatosis in ob/ob mice.
- Drug treatment lowered liver/body weight ratio, triglyceride accumulation, and improved liver pathology markers.
- Inhibition of GSL synthesis prevented new steatosis and reversed existing steatosis in diet-induced obese mice.
Conclusions:
- Inhibiting GSL synthesis ameliorates liver pathology linked to obesity and diabetes.
- Targeting GSL synthesis presents a novel therapeutic strategy for fatty liver disease and NASH.
