Research Article Details
| Article ID: | A10523 |
| PMID: | 31301418 |
| Source: | Life Sci |
| Title: | (5R)-5-hydroxytriptolide ameliorates liver lipid accumulation by suppressing lipid synthesis and promoting lipid oxidation in mice. |
| Abstract: | AIMS: (5R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation. MAIN METHODS: Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism. KEY FINDINGS: LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis. SIGNIFICANCE: Our results provide a novel application of LLDT-8 in improving NAFLD. |
| DOI: | 10.1016/j.lfs.2019.116644 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T22 | Stearoyl-CoA desaturase | SCD | inhibitor | Enzyme | O00767 | SCD_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I15 | 1290 | Bone disease | A connective tissue disease that affects the structure or development of bone or causes an impairment of normal bone function. http://en.wikipedia.org/wiki/Bone_disease | disease of anatomical entity/ musculoskeletal system disease/connective tissue disease | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D201 | L-Carnitine | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D062 | Carnitine complex | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |