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Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism
- Source :
- Am J Physiol Endocrinol Metab
- Publication Year :
- 2019
-
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.
- Subjects :
- Nonalcoholic steatohepatitis
Blood Glucose
Lipopolysaccharides
Male
medicine.medical_specialty
Ceramide
Physiology
Endocrinology, Diabetes and Metabolism
Amitriptyline
Down-Regulation
Inflammation
Diet, High-Fat
Benzylidene Compounds
chemistry.chemical_compound
Mice
Non-alcoholic Fatty Liver Disease
Physiology (medical)
Internal medicine
Diabetes mellitus
medicine
Animals
Sphingosine-1-phosphate
Enzyme Inhibitors
Mice, Knockout
Sphingolipids
Aniline Compounds
Macrophages
medicine.disease
Atherosclerosis
Endocrinology
Sphingomyelin Phosphodiesterase
chemistry
Receptors, LDL
Cytokines
lipids (amino acids, peptides, and proteins)
Acid sphingomyelinase
medicine.symptom
Insulin Resistance
Sphingomyelin
medicine.drug
Research Article
Subjects
Details
- ISSN :
- 15221555
- Volume :
- 318
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Accession number :
- edsair.doi.dedup.....7045ad8a1aa3e07abbaa88c402c4d494