Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol‐related steatohepatitis

Abstract

Background and Aim Alcohol-related liver disease (ALD) is mediated in part by insulin resistance. Attendant dysregulation of lipid metabolism increases accumulation of hepatic ceramides that worsen insulin resistance and compromise the structural and functional integrity of the liver. Insulin and insulin growth factor (IGF) stimulate aspartyl-asparaginyl-β-hydroxylase (AAH), which promotes cell motility needed for structural maintenance and remodeling of the liver. AAH mediates its effects by activating Notch, and in ALD, insulin/IGF signaling, AAH, and Notch are inhibited. Method To test the hypothesis that in ALD, hepatic ceramide load contributes to impairments in insulin, AAH, and Notch signaling, control and chronic ethanol-fed adult Long–Evans rats were treated with myriocin, an inhibitor of serine palmitoyl transferase. Livers were used to assess steatohepatitis, insulin/IGF pathway activation, and expression of AAH–Notch signaling molecules. Results Chronic ethanol-fed rats had steatohepatitis with increased ceramide levels; impairments in signaling through the insulin receptor, insulin receptor substrate, and Akt; and decreased expression of AAH, Notch, Jagged, Hairy–Enhancer of Split-1, hypoxiainducible factor 1α, and proliferating cell nuclear antigen. Myriocin abrogated many of these adverse effects of ethanol, particularly hepatic ceramide accumulation, steatohepatitis, and impairments of insulin signaling through Akt, AAH, and Notch. Conclusions In ALD, the histopathology and impairments in insulin/IGF responsiveness can be substantially resolved by ceramide inhibitor treatments, even in the context of continued chronic ethanol exposure.

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

“…Aspartyl-asparaginyl-␤-hydroxylase (AAH) mediates its effect by activating Notch. Insulin/IGF signaling, AAH, and Notch are inhibited in ALD (99,103,146). Chronic ethanol-fed rats had shown an increased Cer levels and steatohepatitis, with impairments in insulin receptor signaling, insulin receptor substrate, and Akt.…”

“…Insulin-mediated glucose uptake is altered in GD patients, while non-insulin-mediated glucose uptake during euglycemia and hyperglycemia was not distinguished between GD patients and control subjects. Suppression of lipolysis by insulin was less effective in GD (95,99,129). Insulin resistance in GD is not associated with obesity (131,171,175).…”

“…Based on the notion that increased Cer levels may be deleterious, inhibition of de novo Cer synthesis with myriocin affected lipid metabolism in the liver of rats with streptozotocin-induced Type 1 diabetes (91, 95, 150). Myriocin abrogated many of the adverse effects of ethanol, including hepatic Cer accumulation, steatohepatitis, and impairments of insulin signaling (99,103,146).…”

“…The loss of insulin receptor from lipid rafts is due to the accumulation of GM3 (81,85,134). Complex GSLs, such as ganglioside GM3, surround the insulin receptor in the raft membrane compartment and modulate signaling through this receptor (95,99,129). GM3 concentrations, for which GC is the precursor, are elevated in plasma and several cell types in GD (58, 62, 128).…”

“…The accumulation of GC may result to inappropriate cross talk by immune cells and the perpetuation of chronic inflammation in these patients (14,15,91). Accumulated GC in the reticuloendothelial organs leads to chronic antigenic stimulation of the immune system, resulting in polyclonal hypergammaglobulinemia, and monoclonal populations of lymphocytes and plasma cells may arise from this proliferative state (17,18,98,99,146,150). GC increases the risk of multiple myeloma and T cell dysfunction as a result of high levels of ferritin and/or other factors released by monocytes.…”