Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation.

Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (∼20-fold) during the course of oligodendrocyte differentiation and maturation.

Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis.

Conserved residues in the N terminus of lipin-1 are required for binding to protein phosphatase-1c, nuclear translocation, and phosphatidate phosphatase activity.

Lipin-1 is a phosphatidate phosphatase in glycerolipid biosynthesis and signal transduction. It also serves as a transcriptional co-regulator to control lipid metabolism and adipogenesis. These functions are controlled partly by its subcellular distribution.

Differential regulation of the expressions of the PGC-1α splice variants, lipins, and PPARα in heart compared to liver.

Peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α) are crucial transcriptional regulators for genes involved in FA oxidation. Lipin-1 is essential for this increased capacity for β-oxidation in fasted livers, and it is also a phosphatidate phosphatase involved in triacylglycerol and phospholipid synthesis. Little is known about the regulation of these proteins in the heart during fasting, where there is increased FA esterification and oxidation.

Myocardial fatty acid metabolism and lipotoxicity in the setting of insulin resistance.

Management of diabetes and insulin resistance in the setting of cardiovascular disease has become an important issue in an increasingly obese society. Besides the development of hypertension and buildup of atherosclerotic plaques, the derangement of fatty acid and lipid metabolism in the heart plays an important role in promoting cardiac dysfunction and oxidative stress. This review discusses the mechanisms by which metabolic inflexibility in the use of fatty acids as the preferred cardiac substrate in diabetes produces detrimental effects on mechanical efficiency, mitochondrial function, and recovery from ischemia.

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice.

Lipin-1 is the major phosphatidate phosphatase (PAP) in the heart and a transcriptional coactivator that regulates fatty acid (FA) oxidation in the liver. As the control of FA metabolism is essential for maintaining cardiac function, we investigated whether lipin-1 deficiency affects cardiac metabolism and performance. Cardiac PAP activity in lipin-1 deficient [fatty liver dystrophy (fld)] mice was decreased by >80% compared with controls.

Shedding light on the enigma of myocardial lipotoxicity: the involvement of known and putative regulators of fatty acid storage and mobilization.

Excessive fatty acid (FA) uptake by cardiac myocytes is often associated with adverse changes in cardiac function. This is especially evident in diabetic individuals, where increased intramyocardial triacylglycerol (TG) resulting from the exposure to high levels of circulating FA has been proposed to be a major contributor to diabetic cardiomyopathy. At present, our knowledge of how the heart regulates FA storage in TG and the hydrolysis of this TG is limited.

A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.

Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation.