Alcohol-related
liver disease (ALD) is associated with
steatohepatitis and
insulin resistance.
Insulin resistance impairs growth and disrupts lipid metabolism in hepatocytes. Dysregulated lipid metabolism promotes
ceramide accumulation and oxidative stress, leading to lipotoxic states that activate endoplasmic reticulum (ER) stress pathways and worsen
inflammation and
insulin resistance. In a rat model of chronic alcohol feeding, we characterized the effects of a
ceramide inhibitor,
myriocin, on the histopathological and ultrastructural features of
steatohepatitis, and the biochemical and molecular indices of hepatic steatosis,
insulin resistance and ER stress.
Myriocin reduced the severity of alcohol-related
steatohepatitis including the abundance and sizes of lipid droplets and mitochondria,
inflammation and architectural disruption of the ER. In addition,
myriocin-mediated reductions in hepatic
lipid and
ceramide levels were associated with constitutive enhancement of
insulin signalling through the
insulin receptor and IRS-2, reduced hepatic oxidative stress and modulation of ER stress signalling mechanisms. In conclusion,
ceramide accumulation in liver mediates tissue injury,
insulin resistance and lipotoxicity in ALD. Reducing hepatic
ceramide levels can help restore the structural and functional integrity of the liver in chronic ALD due to amelioration of
insulin resistance and ER stress. However, additional measures are needed to protect the liver from alcohol-induced necroinflammatory responses vis-à-vis continued
alcohol abuse.