Proper storage and utilization of lipids is essential to maintain cellular energy homeostasis and perturbation of this balance can lead to a variety of human disorders, including metabolic syndrome. Cellular lipids are generally stored as triglycerides in the form of lipid droplets and are hydrolyzed into fatty acids for energy supply during nutrient deprivation. Recently, macroautophagy (simply called autophagy) has emerged as a major cellular pathway mediating the catabolism of triglycerides and the clearance of lipid droplets (i.e., "macrolipophagy") in hepatocytes and many other cell types. Autophagy ensures the recycling of macromolecules under conditions of nutritional scarcity, as well as the elimination of defective organelles, long- lived proteins, and intracellular protein aggregates. Because of its remarkable efficiency at eliminating cellular "waste" and consuming energy sources, autophagy is increasingly viewed as a pathway that can be exploited for the therapy of various human conditions. The recent discovery of macrolipophagy has raised a number of fundamental questions, including whether there are molecular pathways dedicated to this selective type of autophagy and whether the efficacy of this process is affected by diet and aging. In this proposal, we explore the possibility that the lipid enzyme phospholipase D1 (PLD1) is a positive modulator of macrolipophagy. PLD1 hydrolyzes phosphatidylcholine into the bioactive lipid phosphatidic acid, which regulates signaling and membrane trafficking processes. Our published data indicate that mice lacking PLD1, which are viable, exhibit defects in autophagy in the liver, based on the occurrence of both fewer and smaller autophagosomes in mutant hepatocytes. Remarkably, this phenotype is induced by starvation conditions and is not associated with the accumulation of protein aggregates, as typically observed in mutant mice lacking genes such as Atg5 or Atg7 which are essential for both basal and starvation-induced autophagy. At the mechanistic level, our results suggest that a key function of PLD1-derived phosphatidic acid is to promote the maturation of autophagosomes by facilitating the fusion of these organelles with endosomes/lysosomes. Together with preliminary observations showing that lipid droplets are more prominent in Pld1 knockout liver from starved mice as well as in knockout fibroblasts, our results strongly suggest that PLD1 is implicated in starvation- induced macrolipophagy. In this proposal, we plan to directly test this hypothesis using mice that lack PLD1 selectively in hepatocytes. We also assess the impact of "stressors", such as high fat diet and age, on the efficacy of macrolipophagy, with the prediction that they may further unmask genotype-specific differences in fat accumulation and lipid metabolism. We anticipate our studies will clarify the role of macrolipophagy in the control of lipid metabolism and provide the basis for future work testing whether stimulating the PLD1 pathway can be exploited to promote macrolipophagy in human conditions, such as fatty liver diseases.

Public Health Relevance

Macroautophagy is an essential process that ensures the degradation of many cellular components. Recently, it has been shown to also mediate the clearance of lipid stores in a variety of tissues, including the liver. This phenomenon, called macrolipophagy, has high relevance for human conditions, such as metabolic syndrome. We have identified a candidate regulator for this pathway, phospholipase D1, and propose to characterize the role of this lipid enzyme in fat clearance in the liver using a mouse model lacking this enzyme specifically in this tissue.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Murthy, Mahadev
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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