Intrajejunal infusion of 2-monoacylglycerol reduced food intake without inducing diarrhea in rats.

Some nutrients, such as carbohydrate, fat and protein, are known to stimulate satiety. However, the effect of sn-2-monoacylglycerol (2-MG), one of the digestive products of triglycerides, on food intake is still unclear. In the present study, the effects of 2-MG on food intake and diarrhea were evaluated and compared with long-chain fatty acid (LCFA) in rats by intrajejunal infusion. Intrajejunal infusion of 2-MG reduced food intake. In addition, 2-MG did not induce diarrhea at the condition that it comparably reduced food intake as compared with LCFA. These results suggest that 2-MG stimulates satiety without inducing diarrhea, different from LCFA.

Classical endocannabinoid-like compounds and their regulation by nutrients.

Endocannabinoid-like compounds are structurally related to the true endocannabinoids but do not contain highly unsaturated fatty acids, and they do not bind the cannabinoid receptors. The classical endocannabinoid-like compounds include N-acylethanolamines and 2-monoacylglycerols, and their structural resemblance to the endocannabinoids makes them players in the endocannabinoid system, where they can interfere with the actions of the true endocannabinoids, because they in several cases engage the same synthesizing and degrading enzymes. In addition they have pharmacological actions of their own, which are particularly interesting in a nutritional and metabolic context. Exogenously supplied oleoylethanolamide, palmitoylethanolamide, and linoleoylethanolamide have anorexic effects, and the endogenous formation of these N-acylethanolamines in the small intestine may serve an important role in regulating food intake, through signaling via PPARα and the vagus nerve to the brain appetite center. A chronic high-fat diet will decrease intestinal levels of these anorectic N-acylethanolamines and this may contribute to the hyperphagic effect of high-fat diet; 2-monoacylglycerols mediate endocrine responses in the small intestine; probably trough activation of GPR119 on enteroendocrine cells, and diet-derived 2-monoacylglycerols, for example, 2-oleoylglycerol and 2-palmitoylglycerol might be important for intestinal fat sensing. Whether these 2-monoacylglycerols have signaling functions in other tissues is unclear at present.

Exosome signaling in mammary gland development and cancer.

Exosomes are 40-100 nm intraluminal vesicles that are released by cells upon fusion of multivesicular endosomes (MVEs) with the plasma membrane. The Rab family of small GTPases, including Rab27A and Rab27B, control different steps of exosome release, including transport of MVEs and docking at the plasma membrane. Exosomes are long range message particles that mediate communication between cells in physiological conditions such as mammary gland development and lactation, but also in pathology such as breast cancer. Metastasis is the culmination of cancer progression and involves a complex interaction with the local and distant environment. Exosome messaging contributes to tumor environment interactions such as immune escape, thrombosis and myofibroblast differentiation, thereby modulating metastatic niche preparation.

Bis(monoacylglycero)phosphate, a peculiar phospholipid to control the fate of cholesterol: Implications in pathology.

Bis(monoacylglycero)phosphate (BMP) is a structural isomer of phosphatidylglycerol that exhibits an unusual sn1:sn1' stereoconfiguration, based on the position of the phosphate moiety on its two glycerol units. Early works have underlined the high concentration of BMP in the lysosomal compartment, especially during some lysosomal storage disorders and drug-induced phospholipidosis. Despite numerous studies, both biosynthetic and degradative pathways of BMP remained not completely elucidated. More recently, BMP has been localized in the internal membranes of late endosomes where it forms specialized lipid domains. Its involvement in both dynamics and lipid/protein sorting functions of late endosomes has started to be documented, especially in the control of cellular cholesterol distribution. BMP also plays an important role in the late endosomal/lysosomal degradative pathway. Another peculiarity of BMP is to be naturally enriched in docosahexaenoic acid and/or to specifically incorporate this fatty acid compared to other polyunsaturated fatty acids, which may confer specific biophysical and functional properties to this phospholipid. This review summarizes and updates our knowledge on BMP with an emphasis on its possible implication in human health and diseases, especially in relation to cholesterol homeostasis.

Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.

Anti-atherosclerotic effect of a new synthetic functional oil containing mono- and diacylglycerol from corn oil.

Synthetic oil containing diacylglycerol and monoacylglycerol, called 'functional oil' (FO), was newly produced and evaluated for its putative anti-atherosclerotic potential by in vitro assays and in vivo test using hypercholesterolemic mice (C57BL/6). The FO revealed good inhibitory activities against both liver acyl-CoA:cholesterol acyltransferase and serum lipoprotein-associated phospholipase A2. The FO showed enhanced activities on lipoprotein interaction such as HDL particle rearrangement to produce different sizes of HDL species. In control mice, hypercholesterolemia was induced by consumption of high-cholesterol, high-fat (HCHF) diet that contained 1.25% cholesterol/15% fat/0.5% Na-cholate with or without 5% of corn oil. In experimental mice, 5% of the FO + HCHF diet was fed during the same period. After the 4-week administration of the diet, serum total cholesterol concentration of the FO-fed group decreased by 38 or 20% when compared to the HCHF diet control group or corn oil (99.9% of triacylglycerol) diet group, respectively. The percentage of HDL cholesterol to total cholesterol was 36% of HDL cholesterol in the FO-fed group, while the HCHF control group and corn oil-fed group showed 21 and 25%, respectively. These results indicate that the FO possesses a blood cholesterol-lowering effect in mouse model and inhibition effects against the atherogenic enzymes.

D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains.

D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is a frequently used inhibitor of glycosphingolipid biosynthesis. However, some interesting characteristics of D-PDMP cannot be explained by the inhibition of glycolipid synthesis alone. In the present study, we showed that d-PDMP inhibits the activation of lysosomal acid lipase by late endosome/lysosome specific lipid, bis(monoacylglycero)phosphate (also called as lysobisphosphatidic acid), through alteration of membrane structure of the lipid. When added to cultured fibroblasts, D-PDMP inhibits the degradation of low-density lipoprotein (LDL) and thus accumulates both cholesterol ester and free cholesterol in late endosomes/lysosomes. This accumulation results in the inhibition of LDL-derived cholesterol esterification and the decrease of cell surface cholesterol. We showed that D-PDMP alters cellular cholesterol homeostasis in a glycosphingolipid-independent manner using L-PDMP, a stereoisomer of D-PDMP, which does not inhibit glycosphingolipid synthesis, and mutant melanoma cell which is defective in glycolipid synthesis. Altering cholesterol homeostasis by D-PDMP explains the unique characteristics of sensitizing multidrug resistant cells by this drug.