Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.-T.; Nishimura, A.; Nishida, M. Inhibition of Drp1–Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria–Lipid Droplet Contact. Int. J. Mol. Sci.2024, 25, 5446.
Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.-T.; Nishimura, A.; Nishida, M. Inhibition of Drp1–Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria–Lipid Droplet Contact. Int. J. Mol. Sci. 2024, 25, 5446.
Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.-T.; Nishimura, A.; Nishida, M. Inhibition of Drp1–Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria–Lipid Droplet Contact. Int. J. Mol. Sci.2024, 25, 5446.
Ariyoshi, K.; Nishiyama, K.; Kato, Y.; Mi, X.; Ito, T.; Azuma, Y.-T.; Nishimura, A.; Nishida, M. Inhibition of Drp1–Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria–Lipid Droplet Contact. Int. J. Mol. Sci. 2024, 25, 5446.
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.
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