Location: Children's Nutrition Research CenterTitle: Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue
|XIN, LI - University Of Texas Health Science Center|
|YANG, LI - University Of Texas Health Science Center|
|MAO, ZHENGMEI - University Of Texas Health Science Center|
|PAN, XUEYANG - University Of Minnesota|
|ZHAO, YUESHUI - University Of Texas Health Science Center|
|GU, XUE - University Of Texas Health Science Center|
|ECKEL-MAHAN, KRISTIN - University Of Texas Health Science Center|
|ZUO, ZHONGYUAN - Baylor College Of Medicine|
|TONG, QIANG - Children'S Nutrition Research Center (CNRC)|
|HARTIG, SEAN - Baylor College Of Medicine|
|CHENG, XIAODONG - University Of Texas Health Science Center|
|DU, GUANGWEI - University Of Texas Health Science Center|
|MOORE, DAVID - Baylor College Of Medicine|
|BELLEN, HUGO - Baylor College Of Medicine|
|SESAKI, HIROMI - University Of Texas Health Science Center|
|SUN, KAI - University Of Texas Health Science Center|
Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/6/2020
Publication Date: 4/15/2020
Citation: Xin, L., Yang, L., Mao, Z., Pan, X., Zhao, Y., Gu, X., Eckel-Mahan, K., Zuo, Z., Tong, Q., Hartig, S.M., Cheng, X., Du, G., Moore, D.D., Bellen, H.J., Sesaki, H., Sun, K. 2020. Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue. Federation of American Societies for Experimental Biology Conference. https://doi.org/10.1096/fj.201903100RR.
Interpretive Summary: Dynamin-Related-Protein 1 (DRP1) is known to regulate the fission/spliting of mitochondria, the powerhouse within the cells. In this article, we report that DRP1 proteins can also migrate to another cellular structure called endoplasmic reticulum (ER). One of ER's functions is to synthesize lipid to be stored in lipid droplets within cells, especiall fat cells. We generated mice with fat cell-specific DRP1 mutation. We found that in these mice, the lipid droplets in adipose tissues exhibited less numbers but larger sizes, and failed to change their structures upon cold exposure. We discovered that abnormal lipid droplets occurs because newly generated lipid droplets fail to dissociate from the ER due to the lack of DRP1. Our study uncovered a novel function of DRP1 in the regulation of lipid droplet, which has an impact on adipocyte function.
Technical Abstract: Dynamin-Related-Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to B-adrenergic stimulation. To further investigate the function of DRP1 on ER-lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue-specific DRP1 knockout model (Adipo-Drp1flx/flx). We found that the LDs in adipose tissues of Adipo-Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro-LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo-Drp1flx/flx mice.