Research Article Details
| Article ID: | A20375 |
| PMID: | 26004139 |
| Source: | Exp Gerontol |
| Title: | Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis. |
| Abstract: | Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging. To this end, we analyzed the expression and the subcellular localization of key transcriptional factors involved in lipid metabolism such as ChREBP, Foxo1, Foxa2 and SREBP-1c in the liver of 3- and 24-month old Wistar rats. In addition, we studied the intracellular redistribution of ChREBP in response to fasting/refeeding transition. Old rats were characterized by hepatic steatosis, low serum ketone body levels and postprandial hyperinsulinemia. These observations were paralleled by the cytoplasmic localization and decreased expression of Foxa2, while ChREBP expression was markedly up-regulated and mainly localized in the nucleus. Consequently, the expression of lipogenic and β-oxidation genes was up-regulated or down-regulated, respectively. Besides, the intracellular redistribution of ChREBP in response to fasting/refeeding transition was also impaired in old animals. Additionally, a negative correlation between serum ketone body levels and the nuclear localization of ChREBP was observed only in adult but not in old rats. Taken together, these data suggest that an age-related dysfunctional adaptation of ChREBP, in response to changes in the nutritional state, might contribute to the development of liver steatosis with aging. |
| DOI: | 10.1016/j.exger.2015.05.009 |
| 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 |
| 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 |
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |