| Title: |
The Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation |
| Authors: |
Gupta, Ruby; Mekile, Allatah X.; Patnayak, Rachana L.; Makena, Monish Ram; Bowman, Ray Wesley; White, Cory J.; Lorenzo, Damaris N.; Rao, Rajini |
| Contributors: |
American Diabetes Association |
| Source: |
The Journal of Physiology ; ISSN 0022-3751 1469-7793 |
| Publisher Information: |
Wiley |
| Publication Year: |
2025 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Mutations in NHE6 (human gene name SLC9A6 ) lead to the rare X‐linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na + /H + exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non‐neuronal role is understudied. A common co‐morbidity in CS is low body weight, with body mass index in the 3–5th percentile range. In the present study, we use a Nhe6 KO mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high‐fat diet, Nhe6 KO mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of Nhe6 KO mice on a high‐fat diet. Knockdown of NHE6 (NHE6 KD) in 3T3L1 adipocytes resulted in smaller lipid droplets, pointing to a cell autonomous role in fat accumulation. NHE6 KD adipocytes also exhibit dysregulation of insulin‐responsive uptake of fatty acids, glucose and Fe/transferrin, as well as the cell surface translocation of the corresponding transporters. Furthermore, we observed selective downregulation of key components of the insulin signalling pathway that could be restored using the Na + /H + exchanger mimetic monensin or the V‐ATPase inhibitor bafilomycin, pointing to pH dysregulation as the underlying defect. These findings establish NHE6 as a novel contributor to energy metabolism with implications for CS patients. image Key points NHE6 is an endosomal Na + /H + exchanger mutated in Christianson syndrome. Nhe6 null mice accumulate less fat and weigh less than control animals. In adipocytes, NHE6 knockdown reduces insulin‐stimulated fatty acid and glucose uptake. NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1113/jp289613 |
| DOI: |
10.1113/JP289613 |
| Availability: |
https://doi.org/10.1113/jp289613; https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP289613 |
| Rights: |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.5AAAA5BE |
| Database: |
BASE |