Research Article Details
| Article ID: | A23746 |
| PMID: | 23512965 |
| Source: | Obesity (Silver Spring) |
| Title: | Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression. |
| Abstract: | OBJECTIVES: A spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis is described by nonalcoholic fatty liver disease (NAFLD). With the increased prevalence of obesity, and consequently NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort, a cellular model of hepatic steatosis was developed using HepaRG cells and the resulting biochemical alterations were determined. DESIGN AND METHODS: Using global metabolomic profiling, by means of a novel metabolite extraction procedure, the metabolic profiles in response to the saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty acids, palmitate and oleate (1:2) were examined. RESULTS: We observed elevated levels of the branched chain amino acids, tricarboxylic acid cycle intermediates, sphingosine and acylcarnitines, and reduced levels of carnitine in the steatotic HepaRG model with both palmitate and palmitate:oleate treatments. In addition, elevated levels of diacylglycerols and monoacylglycerols as well as altered bile acid metabolism were selectively displayed by palmitate-induced steatotic cells. CONCLUSIONS: Biochemical changes in pathways important in the transition to hepatic steatosis including insulin resistance, altered mitochondrial metabolism, and oxidative stress are revealed by this global metabolomic approach. Moreover, the utility of this in vitro model for investigating the mechanisms of steatotic progression, insulin resistance, and lipotoxicity in NAFLD was demonstrated. |
| DOI: | 10.1002/oby.20440 |
| 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 |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| 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 | |
|---|---|---|---|---|---|---|---|
| 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 |
| D062 | Carnitine complex | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |