Research Article Details
| Article ID: | A16108 |
| PMID: | 28566408 |
| Source: | J Mol Endocrinol |
| Title: | 5-ALA ameliorates hepatic steatosis through AMPK signaling pathway. |
| Abstract: | 5-Aminolevulinic acid (5-ALA), the first compound in the porphyrin synthesis pathway, has been reported to ameliorate the diabetic state in Otsuka Long-Evans Tokushima Fatty rats by reducing fat pad weight in the retroperitoneal region. Dietary supplementation with 5-ALA has additionally demonstrated the capacity to lower blood glucose and HbA1c levels among subjects with diabetes. The etiology of nonalcoholic fatty liver disease (NAFLD) is complex and its typical characteristics include obesity and insulin resistance. As 5-ALA supplementation has previously normalized glucose and insulin resistance, we sought to investigate whether 5-ALA had potential therapeutic effects on NAFLD and elucidate the signal pathway mediating these effects. To explore these questions, we fed C57BL/6J mice a high-fat diet (HFD) to induce a fatty liver disease and supplemented the diet-induced obese (DIO) mice with 5-ALA. The mice in the presence of 5-ALA demonstrated a decrease in body weight and hepatic lipid content and moderate improvement in glucose homeostasis compared to untreated controls. Further, we found that 5-ALA activated AMPK signaling pathway, which was correlated with enhanced lipolysis and fatty acid β-oxidation. Human hepatocarcinoma cells (HepG2 cells) treated with 5-ALA were additionally used to investigate the mechanics of 5-ALA. Treated cells had a higher expression of lipolysis-related genes, including PGC-1α. Our data indicated that 5-ALA might represent a novel compound that could be useful for the treatment of nonalcoholic fatty liver disease (NAFLD), likely through the restoration of phosphorylation levels of AMPK (Thr172) and acetyl-CoA (ACC) (Ser79), further enhanced PGC1α and CPT1α expression. |
| DOI: | 10.1530/JME-16-0260 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T05 | Peroxisome proliferator-activated receptor gamma | PPARG | agonist | Nuclear hormone receptor | P37231 | PPARG_HUMAN | Details |
| 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 |
| T26 | Thyroid hormone receptor beta | THRB | agonist | Nuclear hormone receptor | P10828 | THB_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D581 | sobetirome | Chemical drug | -- | Thyroid hormone receptor beta agonists | Enhance lipid metabolism | Under investigation | 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 |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D062 | Carnitine complex | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |