Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice

Abstract

<jats:p>Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.</jats:p>

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

“…With the decrease of liver function, the intestinal balance is destroyed [19]. The accumulation of harmful substances such as alcohol leads to liver injury and promotes the secretion of bile acid into the intestinal tract by the liver, thereby regulating the activity of various metabolic reactions in the intestinal tract [2,4,5,13]. The change in the type and number of intestinal flora is an important factor leading to abnormal liver function [20].…”

“…When the body is stimulated by alcohol, the excessive input of lipids leads to the disturbance of lipoprotein synthesis and metabolism in the liver, and the insufficient oxidation of fatty acids, which leads to the deposition of fat in the liver, resulting in fatty liver. Alcoholic fatty liver disease (AFLD) is caused by long-term heavy drinking and is the most common and reversible stage of alcoholic liver disease [1][2][3][4]. Although numerous studies have been conducted on the pathogenesis of alcoholic fatty liver at home and abroad [3], there is still no effective treatment for alcoholic fatty liver in the clinic.…”

Improvement Lipophagy by Restoring Rab7 Cycle: Protective Effects of Quercetin on Ethanol-Induced Liver Steatosis

“…AFLD is associated with lipid metabolism disorder and insulin resistance which lead to alcoholic steatosis [41,42]. Alcohol consumption leads to fatty acid synthesis increase (upregulate SREBP1c in liver [43]) and decrease of fatty acid transport and oxidation (downregulate PPARα [44] and mitochondrial β-oxidation [45]) as the ' rst hit', and chronic alcohol inhibits lipophagy though may activate when acute alcohol administration as a compensatory to against alcoholic liver injury[46, 47].…”

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance&nbsp;

“…With the decrease of liver function, the intestinal balance is destroyed [19]. The accumulation of harmful substances such as alcohol leads to liver injury and promotes the secretion of bile acid into the intestinal tract by the liver, thereby regulating the activity of various metabolic reactions in the intestinal tract [2,4,5,13]. The change in the type and number of intestinal ora is an important factor leading to abnormal liver function [20].…”

“…When the body is stimulated by alcohol, the excessive input of lipids leads to the disturbance of lipoprotein synthesis and metabolism in the liver, and the insu cient oxidation of fatty acids, which leads to the deposition of fat in the liver, resulting in fatty liver. Alcoholic fatty liver disease (AFLD) is caused by long-term heavy drinking and is the most common and reversible stage of alcoholic liver disease [1,2][3] [4]. Although numerous studies have been conducted on the pathogenesis of alcoholic fatty liver at home and abroad [3], there is still no effective treatment for alcoholic fatty liver in the clinic.…”