Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contacts

Kohei Ariyoshi
,
Kazuhiro Nishiyama
,
Yuri Kato
ORCID logo ,
Xinya Mi
,
Tomoya Ito
,
Yasu-Taka Azuma
ORCID logo ,
Akiyuki Nishimura
ORCID logo ,
Motohiro Nishida
*
Version 1 : Received: 14 April 2024 / Approved: 15 April 2024 / Online: 15 April 2024 (08:02:27 CEST)

How to cite: Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.; Nishimura, A.; Nishida, M. Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contacts. Preprints 2024, 2024040918. https://doi.org/10.20944/preprints202404.0918.v1 Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.; Nishimura, A.; Nishida, M. Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contacts. Preprints 2024, 2024040918. https://doi.org/10.20944/preprints202404.0918.v1

Abstract

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, has potency to prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel blocking action of cilnidipine, prevent the palmitic ac-id-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high fat diet-fed mouse livers. These results propose that targeting Drp1-filimin interaction becomes a new strategy for the prevention or treatment of fatty liver disease.

Keywords

lipid droplet; mitochondria fission; fatty liver disease; cilnidipine

Subject

Biology and Life Sciences, Life Sciences

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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