The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Ferrara, Patrick J.; Rong, Xianglu; Maschek, J. Alan; Verkerke, Anthony R.P.; Siripoksup, Piyarat; Song, Houyan; Krishnan, Karthickeyan Chella; Johnson, Jordan M.; Turk, John; Houmard, Joseph A.; Lusis, Aldons J.; Cox, James E.; Shaikh, Saame Raza; Tontonoz, Peter; Funai, Katsuhiko

doi:10.1101/2019.12.23.887232

Cited by 3 publications

(2 citation statements)

References 70 publications

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“…Moreover, the Lands cycle constitutes the major route for incorporation and release of free arachidonic acid (AA, C20:4) and other PUFA into cellular PL, a process that is dependent on intracellular phospholipase A2 (PLA2). Hence, the proper regulation of the Lands cycle is important to control the accumulation of potentially toxic PL and FA, in order to maintain the integrity of cellular membranes (Ferrara et al, 2019; Wang and Tontonoz, 2019).…”

Section: Introductionmentioning

confidence: 99%

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Bartolacci

Andreani

et al. 2021

Preprint

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Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

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Section: Introductionmentioning

confidence: 99%

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Bartolacci

Andreani

et al. 2021

Preprint

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“…Taken together, these findings are consistent with the notion that low mitochondrial PE is sufficient to drive systemic and skeletal muscle metabolic inflexibility. In addition to physical inactivity, highfat diet feeding is also known to induce metabolic flexibility (37). However, phenotypes for whole-body glucose metabolism or skeletal muscle mitochondrial function were not different between control and PSD-Mhet mice after high-fat diet feeding (Figure S6A-P).…”

Section: Muscle Psd Haploinsufficiency Makes Mice More Susceptible To...mentioning

confidence: 98%

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism

Siripoksup,

Cao,

Cluntun

et al. 2024

Journal of Clinical Investigation

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Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans.Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO 2 ) in absence of a change in palmitate-stimulated JO 2 . Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate.We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.

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Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

et al. 2022

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Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either FASN or the Lands cycle in KMLC, promotes ferroptosis, a reactive oxygen species (ROS)- and iron-dependent cell death, characterized by the intracellular accumulation of oxidation-prone PC. Our work indicates that KM dictates a dependency on newly synthesized FA to escape ferroptosis, establishing a targetable vulnerability in KMLC.

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The Lands cycle modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Cited by 3 publications

References 70 publications

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism

Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

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