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

Abstract

of cardiac ATP production ( 1 ). FAs are also incorporated into triacylglycerol (TG), which is stored in lipid droplets. Cardiac TG turnover is rapid ( 2 ) and FAs released from TG can contribute up to 10-20% of ATP production ( 3 ). Plasma FA and TG levels rise in insulin resistance and diabetes ( 4, 5 ), and cardiac FA utilization can increase to supply as much as 90% of ATP ( 6, 7 ). Despite this increase in FAO, FA uptake can exceed the ability of the heart to utilize FAs, leading to excess accumulation of TG in cardiomyocytes ( 6-9 ). The compensatory changes that occur in response to excessive FA availability eventually become maladaptive, and the heart is locked in a pathological and infl exible metabolic state that contributes to cardiac dysfunction ( 6, 7, 10 ). As such, maintenance of metabolic fl exibility is essential for normal cardiac function. Whereas many proteins have been identifi ed to contribute to cardiac FA uptake and metabolism ( 1, 10 ), relatively little information is available about the role of lipin-1 in the heart. Lipin-1 is an important protein involved in regulating both TG synthesis and FAO in other organs ( 11 ).Instead of being considered as mutually antagonistic processes, FAO and TG synthesis are now widely viewed as being companion pathways because augmenting cardiac TG synthesis increases FAO ( 12 ). Moreover, FAs released through lipolysis of endogenous TG stores contribute signifi cantly to FAO ( 3,13 ). Lipin-1 could play a prominent role in this regulation as it is a bifunctional protein involved in regulating both TG synthesis and FAO in the The constant requirement for ATP in the beating heart is satisfi ed by the utilization of diverse substrates, such as fatty acids (FA), glucose, lactate, ketones, and amino acids, with FA oxidation (FAO) providing the majority (50-75%)

Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

“…3). Similarly, Kok et al (46) did not find significant differences in ERK1/2 phosphorylation in fld hearts, suggesting that the effect of phosphatidic acid on ERK phosphorylation may be tissuespecific. ERK1/2 is required for the transcriptional activation of D-type cyclins and plays a fundamental role in the G 0 /G 1 to the S phase transition.…”

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

“…However, animals die within 24 h of treatment, and no differences between wt or fld groups are appreciated. It should be noted in this regard that recent work has shown that fld mice exhibit cardiac dysfunction in vivo (40). Such a defect, together with the well-described cardiac dysfunction induced by high levels of LPS, could explain why fld mice are not protected against high LPS doses (40,41).…”

Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum

“…In lipin-1-deficient mice, the accumulation of the PAP enzyme substrate, PA, in Schwann cells and adipose tissue has been implicated in the pathogenesis of peripheral neuropathy and lipodystrophy, respectively (11,30). This raised the possibility that PA accumulation in lipin-2-KO cerebellum as the mice age contributes to the ataxia.…”