FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.
Lee Seung-Min,Lee Seol Hee,Jung Youngae,Lee Younglang,Yoon Jong Hyun,Choi Jeong Yi,Hwang Chae Young,Son Young Hoon,Park Sung Sup,Hwang Geum-Sook,Lee Kwang-Pyo,Kwon Ki-Sun
Nature communications
Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.
10.1038/s41467-020-19501-6
Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.
Cantalupo Anna,Zhang Yi,Kothiya Milankumar,Galvani Sylvain,Obinata Hideru,Bucci Mariarosaria,Giordano Frank J,Jiang Xian-Cheng,Hla Timothy,Di Lorenzo Annarita
Nature medicine
Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein-coupled receptor-dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II-induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II-induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.
10.1038/nm.3934
Sphingolipids in lipid microdomains and obesity.
Mitsutake Susumu,Igarashi Yasuyuki
Vitamins and hormones
Sphingolipids are major constituents of the plasma membrane, where they are known to form lipid microdomains with cholesterol. Lipid microdomains are thought to be important not only for cellular signal transduction but also for the absorption of extracellular lipids or nutrients. Inhibition of sphingolipid biosynthesis suggested an importance for sphingolipids in fatty acid uptake via lipid microdomains. Additionally, we recently reported that the function of lipid microdomains was dynamically regulated by the sphingomyelin synthase SMS2 on the plasma membrane and that SMS2-deficient mice exhibit resistance against high-fat diet-induced increases in body weight, glucose intolerance, and fatty liver. Now, biosynthesis or metabolism of sphingolipids is thought to be involved in obesity, diabetes, and cardiovascular diseases. In this review, I focus on the functions of sphingolipids in lipid microdomains and describe their contributions to obesity and diabetes.
10.1016/B978-0-12-407766-9.00012-2
Meeting Report - The 2019 FEBS special meeting on sphingolipid biology: sphingolipids in physiology and pathology.
D'Angelo Giovanni,Clarke Christopher J,Silva Liana C
Journal of cell science
Sphingolipids are a fundamental class of molecules that are involved in structural, organizational and signaling properties of eukaryotic membranes. Defects in their production or disposal lead to acquired and inherited human diseases. A growing community of scientists has embraced the challenge to dissect different aspects of sphingolipid biology using a variety of approaches, and a substantial part of this community met last May in the beautiful town of Cascais in Portugal. Over 200 scientists from 26 countries animated the conference, held in a 15th century citadel, sharing their data and opinions on the current understanding and future challenges in sphingolipid research. Here, we report some of their contributions to provide the readers with a bird's-eye view of the themes discussed at the meeting.
10.1242/jcs.235705
Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice.
Hojjati Mohammad Reza,Li Zhiqiang,Zhou Hongwen,Tang Songshan,Huan Chongmin,Ooi Everlyn,Lu Shendi,Jiang Xian-Cheng
The Journal of biological chemistry
Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.
10.1074/jbc.M412348200
Sphingolipids and cardiovascular diseases: lipoprotein metabolism, atherosclerosis and cardiomyopathy.
Jiang Xian-Cheng,Goldberg Ira J,Park Tae-Sik
Advances in experimental medicine and biology
Heart disease is widely believed to develop from two pathological processes. Circulating lipoproteins containing the nondegradable lipid, cholesterol, accumulate within the arterial wall and perhaps are oxidized to more toxic lipids. Both lipid accumulation and vascular reaction to the lipids lead to the gradual thickening of the vascular wall. A second major process that in some circumstances is a primary event is the development of a local inflammatory reaction. This might be a reaction to vessel wall injury that accompanies infections, immune disease, and perhaps diabetes and renal failure. In this chapter, we will focus on the relationship between de novo synthesis of sphingolipids and lipid metabolism, atherosclerosis, and cardiomyopathy.
10.1007/978-1-4614-0650-1_2
Sphingolipid signalling in the cardiovascular system: good, bad or both?
Alewijnse Astrid E,Peters Stephan L M
European journal of pharmacology
Sphingolipids are biologically active lipids that play important roles in various cellular processes and the sphingomyelin metabolites ceramide, sphingosine and sphingosine-1-phosphate can act as signalling molecules in most cell types. With the recent development of the immunosuppressant drug FTY720 (Fingolimod) which after phosphorylation in vivo acts as a sphingosine-1-phosphate receptor agonist, research on the role of sphingolipids in the immune and other organ systems was triggered enormously. Since it was reported that FTY720 induced a modest, but significant transient decrease in heart rate in animals and humans, the question was raised which pharmacological properties of drugs targeting sphingolipid signalling will affect cardiovascular function in vivo. The answer to this question will most likely also indicate what type of drug could be used to treat cardiovascular disease. The latter is becoming increasingly important because of the increasing population carrying characteristics of the metabolic syndrome. This syndrome is, amongst others, characterized by obesity, hypertension, atherosclerosis and diabetes. As such, individuals with this syndrome are at increased risk of heart disease. Now numerous studies have investigated sphingolipid effects in the cardiovascular system, can we speculate whether certain sphingolipids under specific conditions are good, bad or maybe both? In this review we will give a brief overview of the pathophysiological role of sphingolipids in cardiovascular disease. In addition, we will try to answer how drugs that target sphingolipid signalling will potentially influence cardiovascular function and whether these drugs would be useful to treat cardiovascular disease.
10.1016/j.ejphar.2008.02.089
Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction.
Dekker Mark J,Baker Chris,Naples Mark,Samsoondar Josh,Zhang Rianna,Qiu Wei,Sacco Jennifer,Adeli Khosrow
Atherosclerosis
Sphingolipids have emerged as important bioactive lipid species involved in the pathogenesis of type 2 diabetes and cardiovascular disease. However, little is known of the regulatory role of sphingolipids in dyslipidemia of insulin-resistant states. We employed hamster models of dyslipidemia and insulin resistance to investigate the role of sphingolipids in hepatic VLDL overproduction, induction of insulin resistance, and inflammation. Hamsters were fed either a control chow diet, a high fructose diet, or a diet high in fat, fructose and cholesterol (FFC diet). They were then treated for 2 weeks with vehicle or 0.3 mg/kg myriocin, a potent inhibitor of de novo sphingolipid synthesis. Both fructose and FFC feeding induced significant increases in hepatic sphinganine, which was normalized to chow-fed levels with myriocin (P < 0.05); myriocin also lowered hepatic ceramide content (P < 0.05). Plasma TG and cholesterol as well as VLDL-TG and -apoB100 were similarly reduced with myriocin treatment in all hamsters, regardless of diet. Myriocin treatment also led to improved insulin sensitivity and reduced hepatic SREBP-1c mRNA, though it did not appear to ameliorate the activation of hepatic inflammatory pathways. Importantly, direct treatment of primary hamster hepatocytes ex vivo with C2 ceramide or sphingosine led to an increased secretion of newly synthesized apoB100. Taken together, these data suggest that a) hepatic VLDL-apoB100 overproduction may be stimulated by ceramides and sphingosine and b) inhibition of sphingolipid synthesis can reduce circulating VLDL in hamsters and improve circulating lipids--an effect that is possibly due to improved insulin signaling and reduced lipogenesis but is independent of changes in inflammation.
10.1016/j.atherosclerosis.2013.01.041
Sphingolipid signaling in metabolic disorders.
Hla Timothy,Dannenberg Andrew J
Cell metabolism
Sphingolipids, ubiquitous membrane lipids in eukaryotes, carry out a myriad of critical cellular functions. The past two decades have seen significant advances in sphingolipid research, and in 2010 a first sphingolipid receptor modulator was employed as a human therapeutic. Furthermore, cellular signaling mechanisms regulated by sphingolipids are being recognized as critical players in metabolic diseases. This review focuses on recent advances in cellular and physiological mechanisms of sphingolipid regulation and how sphingolipid signaling influences metabolic diseases. Progress in this area may contribute to new understanding and therapeutic options in complex diseases such as atherosclerosis, diabetes, metabolic syndromes, and cancer.
10.1016/j.cmet.2012.06.017
Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation.
Norris Gregory H,Blesso Christopher N
Nutrients
Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti-inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism.
10.3390/nu9111180
Endothelial Sphingolipid De Novo Synthesis Controls Blood Pressure by Regulating Signal Transduction and NO via Ceramide.
Cantalupo Anna,Sasset Linda,Gargiulo Antonella,Rubinelli Luisa,Del Gaudio Ilaria,Benvenuto Domenico,Wadsack Christian,Jiang Xiang-Chen,Bucci Maria Rosaria,Di Lorenzo Annarita
Hypertension (Dallas, Tex. : 1979)
Ceramides are sphingolipids that modulate a variety of cellular processes via 2 major mechanisms: functioning as second messengers and regulating membrane biophysical properties, particularly lipid rafts, important signaling platforms. Altered sphingolipid levels have been implicated in many cardiovascular diseases, including hypertension, atherosclerosis, and diabetes mellitus-related conditions; however, molecular mechanisms by which ceramides impact endothelial functions remain poorly understood. In this regard, we generated mice defective of endothelial sphingolipid de novo biosynthesis by deleting the Sptlc2 (long chain subunit 2 of serine palmitoyltransferase)-the first enzyme of the pathway. Our study demonstrated that endothelial sphingolipid de novo production is necessary to regulate (1) signal transduction in response to NO agonists and, mainly via ceramides, (2) resting eNOS (endothelial NO synthase) phosphorylation, and (3) blood pressure homeostasis. Specifically, our findings suggest a prevailing role of C16:0-Cer in preserving vasodilation induced by tyrosine kinase and GPCRs (G-protein coupled receptors), except for Gq-coupled receptors, while C24:0- and C24:1-Cer control flow-induced vasodilation. Replenishing C16:0-Cer in vitro and in vivo reinstates endothelial cell signaling and vascular tone regulation. This study reveals an important role of locally produced ceramides, particularly C16:0-, C24:0-, and C24:1-Cer in vascular and blood pressure homeostasis, and establishes the endothelium as a key source of plasma ceramides. Clinically, specific plasma ceramides ratios are independent predictors of major cardiovascular events. Our data also suggest that plasma ceramides might be indicative of the diseased state of the endothelium.
10.1161/HYPERTENSIONAHA.119.14507