Gramd1c-KO Mouse

Gramd1c, also known as Aster-C, is an endoplasmic reticulum (ER)-localized cholesterol transport protein. It plays a crucial role in regulating autophagy initiation and mitochondrial bioenergetics. It is involved in the non-vesicular transport of cholesterol between different cellular compartments, contributing to the maintenance of cellular cholesterol distribution and homeostasis. The protein may function in several pathways related to lipid metabolism and cell survival [1,2,4].

In mouse models, global deletion of Gramd1c (Gramd1c-/-) shows no significant alterations in fecal, liver, or plasma cholesterol levels under different dietary cholesterol conditions. However, under low dietary cholesterol, there are modest changes in select bile acid species and elevated cortisol levels. This indicates that Aster-C alone has a minor role in whole-body cholesterol balance but can impact certain aspects of metabolism when dietary cholesterol is limited [5]. In cell-based studies, short-term cholesterol depletion induces autophagy, and GRAMD1C functions as a negative regulator of starvation-induced autophagy. Its cholesterol-transporting VASt domain and membrane-binding GRAM domain are required for suppressing autophagy initiation. Cells lacking GRAMD1C show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting a role in cholesterol transfer at ER-mitochondria contact sites [1,2]. In addition, in Parkinson's disease (PD) research, GRAMD1C is upregulated in PD patients and 6-OHDA-induced PC12 cells. Knocking down GRAMD1C expression reduces 6-OHDA-induced apoptosis in PC12 cells, suggesting its involvement in the apoptotic pathway in PD [3].

In summary, Gramd1c is mainly involved in cholesterol transport-related functions, which have implications for autophagy, mitochondrial bioenergetics, and whole-body cholesterol balance to some extent. Model-based research, including mouse models and cell-based experiments, has revealed its significance in diseases like Parkinson's disease, highlighting its potential as a therapeutic target in related disease areas.

References:

1. Charsou, Chara, Ng, Matthew Yoke Wui, Simonsen, Anne. 2022. Regulation of autophagosome biogenesis and mitochondrial bioenergetics by the cholesterol transport protein GRAMD1C. In Autophagy, 19, 2159-2161. doi:10.1080/15548627.2022.2155020. https://pubmed.ncbi.nlm.nih.gov/36469687/

2. Ng, Matthew Yoke Wui, Charsou, Chara, Lapao, Ana, Munson, Michael J, Simonsen, Anne. 2022. The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics. In Nature communications, 13, 6283. doi:10.1038/s41467-022-33933-2. https://pubmed.ncbi.nlm.nih.gov/36270994/

3. He, Hui, Zhang, Bo, Wang, Xiang, Chen, Lulu. 2024. Knocking down GRAMD1C expression reduces 6-OHDA-induced apoptosis in PC12 cells. In Toxicology research, 13, tfae051. doi:10.1093/toxres/tfae051. https://pubmed.ncbi.nlm.nih.gov/38638451/

4. Naito, Tomoki, Yang, Haoning, Koh, Dylan Hong Zheng, Lu, Lei, Saheki, Yasunori. 2023. Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites. In Nature communications, 14, 5867. doi:10.1038/s41467-023-41213-w. https://pubmed.ncbi.nlm.nih.gov/37735529/

5. Banerjee, Rakhee, Hohe, Rachel C, Cao, Shijie, Parini, Paolo, Brown, J Mark. 2024. The nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance. In Frontiers in physiology, 15, 1371096. doi:10.3389/fphys.2024.1371096. https://pubmed.ncbi.nlm.nih.gov/38694206/