Inhibition of acid sphingomyelinase activity ameliorates endothelial dysfunction in <i>db/db</i> mice

Jiang, Meng; Huang, Shanya; Liu, Qiaoshu; Lei, Minxiang

doi:10.1042/bsr20182144

Cited by 19 publications

(23 citation statements)

References 29 publications

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“…Prior studies of obese rodents revealed that ceramide inhibition could improve obesity-related metabolic abnormalities such as insulin resistance, hyperglycemia, and hyperlipidemia (9, 19, 21–23). Prior studies also revealed that blunting de novo ceramide synthesis could ameliorate hepatic steatosis in obese animals (6, 11).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Jiang

Liu

et al. 2019

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic disorder diseases, which include a histological spectrum of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Dysregulated metabolism of sphingomyelin in the liver plays a critical role in the pathogenesis of NAFLD. Ceramides are central molecules of sphingolipid biosynthesis and catabolism and play an important role in insulin resistance, apoptosis, and inflammation. In addition, apoptosis is a main contributor to the development of NAFLD. This study detected whether the inhibition of ceramide synthesis ameliorated hepatic steatosis and fibrosis in rats with NAFLD. Sprague-Dawley rats were used to establish the NAFLD model. Here, we showed that hepatic ceramide, steatosis, and fibrosis increased in liver tissue from rats with NAFLD. Chronic treatment with myriocin inhibited ceramide and lipid accumulation and improved fibrosis in liver tissue samples of high fat diet (HFD)-fed rats. In addition, hepatic inflammation and apoptosis were markedly ameliorated in HFD-fed rats treated with myriocin. Furthermore, myriocin treatment regulated the expression of pro-apoptosis and anti-apoptosis proteins by inactivating the c-Jun N-terminal kinase (JNK) signaling pathway in the liver of HFD-fed rats. Collectively, ceramide plays an important role in the pathogenesis of NASH and may represent a potential therapeutic strategy to prevent NAFLD.

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Section: Discussionmentioning

confidence: 99%

Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Jiang

Liu

et al. 2019

Front. Endocrinol.

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“…ASM also plays a major role in the development of many other disorders such as cardiovascular and metabolic diseases. Its downregulation was reported to alleviate vascular endothelial insulin resistance in diabetic rats [152] and improve vascular dysfunction in diabetic mice [153]. Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis as induced by high-fat diet and lipopolysaccharide in mice [154].…”

Section: Assays For Studies Of Asm Inhibitorsmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

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Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.

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“…Leptin can induce vasodilatation through the Ob-Rb/STAT3/Akt signal pathways [ 57 ], and endothelial leptin resistance impairs eNOS activation and reduces endothelium-dependent vasodilation [ 58 ]. Moreover, the ASM/ceramide pathway mediates vascular dysfunction by regulating the Akt/eNOS/NO signaling pathway, and the inhibition of the ASM/ceramide pathway can improve endothelium-dependent vasodilation [ 59 , 60 ]. Here, the levels of serum eNOS and NO in HFD-fed rats were normalized by AMI and IMI.…”

Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats

Cai

2019

Acta Pharmacol Sin

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Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg −1 per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.

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Inhibition of acid sphingomyelinase activity ameliorates endothelial dysfunction in db/db mice

Cited by 19 publications

References 29 publications

Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats

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