High-fat diet-associated cognitive decline: Is zinc finger protein 1 (ZPR1) the molecular connection?

• Main Authors: Mythri Chittilla, Nuraly S. Akimbekov, Mohammed S. Razzaque
• Format: Article
• Language: English
• Published: Elsevier 2021-01-01
• Series: Current Research in Physiology
• Subjects: ZPR1; High-fat diet; Neuronal death; Cognitive function
• Online Access: http://www.sciencedirect.com/science/article/pii/S2665944121000250

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.