The endogenous lipid metabolism network is associated with the occurrence and progression of malignancies. Endocannabinoids and ceramides have demonstrated their anti-proliferative and pro-apoptotic properties in a series of cancer studies. The aim of the present study was to evaluate the expression patterns of endocannabinoids and endogenous ceramides in 67 pairs of human hepatocellular carcinoma (HCC) tissues and non-cancerous counterpart controls. Anandamide (AEA), the major endocannabinoid, was reduced in tumor tissues, probably due to the high expression and activity of fatty acid amide hydrolase. Another important endocannabinoid, 2-arachidonylglycerol (2-AG), was elevated in tumor tissues compared with non-tumor controls, indicating that the biosynthesis of 2-AG is faster than the degradation of 2-AG in tumor cells. Furthermore, western blot analysis demonstrated that cannabinoid receptor 1 was downregulated, while cannabinoid receptor 2 was elevated in HCC tissues, in accordance with the alterations in the levels of AEA and 2-AG, respectively.

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Sleep loss is a key factor associated with dry eye. Use of a "stick over water" mouse model revealed that sleep deprivation induces accumulation of lipids, hypertrophy, and dysfunction of the lacrimal gland. These changes result in decreased tear production and dry eye clinical signs. The specific pathophysiological mechanisms that contribute to dry eye remain unclear. In this study, we found that sleep deprivation decreased endogenous lipid palmitoylethanolamide (PEA) expression in the lacrimal gland. The reduced expression was mainly attributed to the decreased expression of N-acylated phosphatidylethanolamine-phospholipase D, the synthetic enzyme of PEA. Exogenous PEA treatment restored local lipid metabolism homeostasis in the lacrimal gland. This change was accompanied by reduced lipid deposition, maintenance of the endoplasmic reticulum and mitochondrial morphology, and improved acinar cell secretory function. PEA treatment also prevented damage to corneal barrier function and improved the dry eye clinical signs caused by sleep deprivation. The nuclear receptor peroxisome proliferator-activated receptor-a (PPAR-a) was found to mediate the PEA-associated improvements. We describe here for the first time that PEA is involved in sleep deprivation-induced lacrimal gland pathogenesis and dry eye development. PEA and its metabolizing enzymes may serve as adjunctive therapeutic targets for treatment of dry eye.