Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier
| Autor: | Yangzom D. Bhutia, Vadivel Ganapathy, Jonathan Kopel, Sathish Sivaprakasam |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Aging Protein Conformation Biochemistry Mice 0302 clinical medicine Neoplasms Drosophila Proteins Glycolysis Review Articles Beta oxidation Cancer Dicarboxylic Acid Transporters Mice Knockout Neurons Diabetes & Metabolic Disorders chemistry.chemical_classification 0303 health sciences Symporters Glutamate receptor medicine.anatomical_structure Female Spasms Infantile Acetylcholine medicine.drug medicine.medical_specialty brain Citric Acid Cycle Longevity Biology liver Blood–brain barrier Bone and Bones Citric Acid metabolic syndrome 03 medical and health sciences Species Specificity NACT/SLC13A5/mINDY Internal medicine Diabetes Mellitus medicine Animals Humans Dental Enamel Molecular Biology 030304 developmental biology Ion Transport Infant Newborn Fatty acid Transporter Cell Biology blood-brain barrier Fatty Liver Disease Models Animal Germ Cells Endocrinology chemistry Gluconeogenesis Mutation Hepatocytes EIEE25/DEE25 Cell Membranes Excitation & Transport 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | NaCT/SLC13A5 is a Na+-coupled transporter for citrate in hepatocytes, neurons, and testes. It is also called mINDY (mammalian ortholog of ‘I'm Not Dead Yet’ in Drosophila). Deletion of Slc13a5 in mice leads to an advantageous phenotype, protecting against diet-induced obesity, and diabetes. In contrast, loss-of-function mutations in SLC13A5 in humans cause a severe disease, EIEE25/DEE25 (early infantile epileptic encephalopathy-25/developmental epileptic encephalopathy-25). The difference between mice and humans in the consequences of the transporter deficiency is intriguing but probably explainable by the species-specific differences in the functional features of the transporter. Mouse Slc13a5 is a low-capacity transporter, whereas human SLC13A5 is a high-capacity transporter, thus leading to quantitative differences in citrate entry into cells via the transporter. These findings raise doubts as to the utility of mouse models to evaluate NaCT biology in humans. NaCT-mediated citrate entry in the liver impacts fatty acid and cholesterol synthesis, fatty acid oxidation, glycolysis, and gluconeogenesis; in neurons, this process is essential for the synthesis of the neurotransmitters glutamate, GABA, and acetylcholine. Thus, SLC13A5 deficiency protects against obesity and diabetes based on what the transporter does in hepatocytes, but leads to severe brain deficits based on what the transporter does in neurons. These beneficial versus detrimental effects of SLC13A5 deficiency are separable only by the blood-brain barrier. Can we harness the beneficial effects of SLC13A5 deficiency without the detrimental effects? In theory, this should be feasible with selective inhibitors of NaCT, which work only in the liver and do not get across the blood-brain barrier. |
| Databáze: | OpenAIRE |
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