Research Article Details
| Article ID: | A01435 |
| PMID: | 34746842 |
| Source: | Curr Res Physiol |
| Title: | High-fat diet-associated cognitive decline: Is zinc finger protein 1 (ZPR1) the molecular connection? |
| Abstract: | Zinc finger protein 1 (ZPR1) is required for cellular replication and viability. Recently, ZPR1 variant rs964184 has been repeatedly linked to high plasma triglyceride levels, metabolic syndrome, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD), suggesting its involvement in lipid metabolism. This article attempts to explain how ZPR1 contributes to the mechanism of high-fat diet-associated cognitive decline through three premises: i) high-fat diet results in cognitive decline, ii) ZPR1 deficiency also results in cognitive decline, and iii) high-fat diet results in ZPR1 deficiency. Therefore, ZPR1 has the potential to be the connection between high-fat diet and cognitive decline. The two modalities of cognitive decline caused by low concentrations of ZPR1 are reduced brain-derived growth factor (BDNF) synthesis and neuron death, both occurring in the hippocampus. Downregulation of ZPR1 may lead to decreased synthesis of BDNF due to reduced concentrations of peroxisome proliferator-activated receptor-gamma (PPAR-γ), tropomyosin receptor kinase B (Trk B), and cAMP response element-binding protein (CREB), resulting in reduced ability to form and retain long-term memory as well as reduced neuroplasticity. Likewise, low concentrations of ZPR1 facilitate neuron death by producing lower amount of spinal motor neuron (SMN) protein, causing genomic instability, activating mixed-lineage protein kinase 3 (MLK3), mitogen-activated protein kinase 7 (MKK7), and c-Jun N-terminal kinase 3 (JNK3) signal cascade, and ultimately resulting in the activation of Caspase 3. |
| DOI: | 10.1016/j.crphys.2021.09.004 |
| 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 |
|---|
| 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 | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D395 | Zinc | Chemical drug | DB01593 | PSPH; CCS; HDAC1 cofactor; HDAC4 cofactor; INS; UTRN; ASPA cofactor; TP73 cofactor; A2M; AGT; APOBR; APOE; APOL1; C3; C5; CFB; CFH; CFI; CLU; CP; CPN2; DSP; F12; F13B; FGA; GSN; HBB; HPR; JUP; SELENOP; TTR; VTN | -- | Under clinical trials | Details |