Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.

Abstract

Objective: Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver.

Methods: In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice.

Results: Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis.

Conclusion: Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.