Abstract
AbstractLipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanol-fed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LD-associated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanol-fed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles.
Highlights
Refeeding or fasting after ethanol withdrawal attenuated hepatic steatosis We tested whether refeeding ethanol-fed rats the liquid control diet for 7 days (i.e., “7-day refed”) or fasting them for 48 h (i.e., “ethanol-fast”) after ethanol withdrawal attenuates alcohol-induced fatty liver
Long perceived as inert fat-storing intracellular vesicles, lipid droplet (LD) gained attention for their role in regulating energy homeostasis in healthy liver cells and their oversupply in unhealthy hepatocytes of rodents or humans with alcohol- or diet-induced fatty liver [31]
Recent understanding of LD biology reveals that the lipid and protein compositions of LDs are highly dynamic
Summary
Carcinoembryonic antigen-related cell adhesion molecule 1, Plin-3, CIDEB, HSD17β7, HSD17β13 and G0s2 proteins, each elevated by ethanol feeding (Fig. 4B) were all normalized to control levels in hepatic LDs from 7-day refed and ethanol-fast rats (Fig. 5E).
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