ArticleAmerican journal of physiology. Endocrinology and metabolism2020
Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism.
Article in American journal of physiology. Endocrinology and metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 43 citations in OpenAlex.
- Sphingolipid Metabolism in Obesity: Bidirectional Regulation and Comparative Perspectives on Plant Sphingolipids.Nutrients · 2026Review
- Ginsenoside F1 ameliorates nonalcoholic fatty liver disease by activating the AMPK/PGC-1α pathway and autophagy.In vitro cellular & developmental biology. Animal · 2026Article
- Opaganib Protects Against High-Fat Diet-Induced Hypercholesterolemia and Liver Steatosis in Mice.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Acid sphingomyelinase downregulation alleviates diabetic myocardial fibrosis in mice.Molecular and cellular biochemistry · 2025Article
- Emerging roles of the acid sphingomyelinase/ceramide pathway in metabolic and cardiovascular diseases: Mechanistic insights and therapeutic implications.World journal of cardiology · 2025Review
- Exosomal miR-155-5p promote the occurrence of carotid atherosclerosis.Journal of cellular and molecular medicine · 2024Article
- Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?Nutrients · 2024Review
- Progress in the Study of Animal Models of Metabolic Dysfunction-Associated Steatotic Liver Disease.Nutrients · 2024Review
- Influence of metabolic state and body composition on the action of pharmacological treatment of migraine.The journal of headache and pain · 2024Review
- The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction.Cardiovascular drugs and therapy · 2024Article
- Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.Cellular and molecular life sciences : CMLS · 2024Review
- Inhibition of the HFrontiers in immunology · 2024Article
- Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis.Frontiers in endocrinology · 2024Review
- The Presence of Periodontitis Exacerbates Non-Alcoholic Fatty Liver Disease via Sphingolipid Metabolism-Associated Insulin Resistance and Hepatic Inflammation in Mice with Metabolic Syndrome.International journal of molecular sciences · 2023Article
- Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis.Cardiovascular diabetology · 2023Article
- Article
- Molecular Advances in MAFLD-A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis.International journal of molecular sciences · 2022Review
- Inflammation Induced by Lipopolysaccharide and Palmitic Acid Increases Cholesterol Accumulation via Enhancing Myeloid Differentiation Factor 88 Expression in HepG2 Cells.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Curcumin alleviates lipopolysaccharides-induced inflammation and apoptosis in vascular smooth muscle cells via inhibition of the NF-κB and JNK signaling pathways.Inflammopharmacology · 2022Article
- Inhibition of acid sphingomyelinase by imipramine abolishes the synergy between metabolic syndrome and periodontitis on alveolar bone loss.Journal of periodontal research · 2022Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
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Registered trials
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