Mitochondrial Complex I modulator (CIM) reduces lipid accumulation and inflammation in MCD-diet fed rats

• Published in: Digestive and liver disease 2023-03, Vol.55, p.S29-S30
• Main Authors: Di Pasqua, L.G., Bosco, O., Cagna, M., Sun, P., Kauschke, S.G., Vairetti, M., Croce, A.C., Ferrigno, A.
• Format: Article
• Language: English
• ISSN: 1590-8658; 1878-3562
• DOI: 10.1016/j.dld.2023.01.055

Inflammation, ROS and mitochondrial dysfunction play a key role in NAFLD progression. Currently no treatments are available, but the finding that metformin targets mitochondrial Complex I opens a new challenge for the research. Aim of this work was to investigate if the selective modulation of mitochondrial Complex I, which is the main ROS producer in mitochondria, could play a role in decreasing lipid accumulation and NAFLD progression. male Wistar rats, fed by a Methionine and Choline deficient (MCD) diet or Control diet for 6 weeks, were orally administered, starting from the fourth week, with Complex I Modulator (CIM, Boehringer Ingelheim) 10mg/Kg/day or vehicle for 3 weeks. TBARS, ROS, ATP content, NAD(P)H bound/free ratio, Nitrate and Nitrite, total lipid content and the area of lipid droplets in the liver were evaluated. TBARS increased in MCD-treated rats compared with Controls, without changes after CIM administration. ROS increased in MCD groups, but a significant reduction in CIM-treated Controls was detected. ATP decreased in CIM-treated Controls, however no differences were appreciated in MCD-treated groups. The same trend was observed for NAD(P)H bound/free ratio. Nitrate and Nitrite were reduced in CIM-treated MCD rats, compared with vehicle-treated MCD rats. Total lipid content displayed a significant reduction in CIM-treated MCD rats and a significant reduction in lipid droplet areas was also observed in CIM-treated MCD rats, compared with untreated MCD group. Inflammatory cell infiltration was significantly reduced in CIM-treated MCD rats and a significant decrease in AST and ALT was observed in CIM-treated Control rats, compared with untreated controls. This is the first attempt to demonstrate a possible role of Complex I Modulator in reducing lipid accumulation and inflammation in a model of benign steatosis, although further investigation are needed to clarify the underling mechanisms of this process.