Abstract
Obesogenic lipids and the sphingolipid ceramide have been implicated as potential cofactors in alcoholic liver disease (ALD) patients. However, the mechanisms by which these lipids modulate lipid trafficking in ethanol-treated human liver cells to promote steatosis, an early stage of ALD, are poorly understood. We measured fatty acid (FA) uptake, triglyceride export, FA synthesis and FA oxidation in human hepatoma (VL-17A) cells in response to ethanol and the exogenous lipids oleate, palmitate and C2 ceramide. We found that in combination with ethanol, both oleate and palmitate promote lipid droplet accumulation while C2 ceramide inhibits lipid droplet accumulation by enhancing FA oxidation. Further, using both a pharmacologic and siRNA approach to reduce peroxisome proliferator-activated receptors α (PPARα) gene expression, we demonstrate that C2 ceramide abrogates ethanol-mediated suppression of FA oxidation through an indirect PPARα mechanism. Together, these data suggest that lipids interact differentially with ethanol to modulate hepatocellular lipid droplet accumulation and may provide novel targets for preventing the earliest stage of alcoholic liver disease, alcoholic steatosis.
Highlights
Chronic ethanol consumption can cause alcoholic steatosis, the excessive accumulation of lipids within hepatocellular cytoplasmic lipid droplets (LDs)
Chronic ethanol intake has been demonstrated to promote TG accumulation within these LDs by enhancing fatty acid (FA) uptake from the circulation[2], reducing export of the TG-rich very low density lipoprotein (VLDL) particle[3], upregulating pathways involved in de novo lipogenesis (DNL)[2,4,5,6], inhibiting FA β-oxidation[6], and upregulating the major hepatic LD protein Perilipin 2 (PLIN2)[7,8], a protein we previously demonstrated is required for the development of alcoholic steatosis in mice[7]
We have previously reported in a PLIN2 knock-out mouse model that reducing hepatocellular LD storage capacity prevents alcoholic steatosis and improves glucose tolerance and insulin resistance[7], suggesting that modulation of steatosis itself may lower the risk of advanced alcoholic liver disease (ALD)
Summary
Chronic ethanol consumption can cause alcoholic steatosis, the excessive accumulation of lipids within hepatocellular cytoplasmic lipid droplets (LDs). While a positive correlation between dietary linoleic acid content and liver damage in alcohol fed rats has been demonstrated[13], there is little molecular detail on how specific FAs alter lipid trafficking. It is unknown whether other lipid species interact with ethanol to either promote or ameliorate alcoholic steatosis. Ceramides have not been associated with ALD pathogenesis, short-chain ceramides such as C2 have been used experimentally because they are cell permeable[27] and mimic the physiological effects of long-chain ceramides, such as induction of apoptosis[28] and inhibition of insulin signaling[28,29]. The mechanism by which ceramides modulate ethanol’s effects on hepatic lipid metabolism is unknown
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