Related Experiment Video
Updated: Jan 29, 2026
Handling Techniques to Reduce Stress in Mice
Published on: September 25, 2021
Complex I Modulator BI4500 Reduces MASH by Limiting Oxidative Stress and Reprogramming Lipid Metabolism via AMPK in
Laura Giuseppina Di Pasqua1, Sofia Lotti1, Michelangelo Trucchi1
1Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
Background:
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a multifactorial liver disease in which mitochondrial dysfunction, oxidative stress, and inflammation play key roles in driving the progression toward metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Dysfunctional mitochondria generate excess reactive oxygen species (ROS), impair antioxidant defenses, activate pro-inflammatory pathways and hepatic stellate cells, and perpetuate liver injury. Mitochondrial Complex I is a major ROS source, particularly under conditions of dysregulated energy metabolism. Since Complex I inhibition by metformin was shown to reduce ROS and activate the adenosine monophosphate-activated protein kinase (AMPK), this study aimed to evaluate whether a novel Complex I Modulator (CIM, BI4500) could attenuate oxidative stress, inflammation, and consequently reduce lipid accumulation and fibrosis in a methionine- and choline-deficient diet (MCD)-fed rat model of MASH.
Methods:
Rats were fed an MCD or an isocaloric control diet for six weeks. From week four, animals received daily oral treatment with CIM (10 mg/kg) or vehicle (Natrosol). At the endpoint, liver tissue was collected for histological, biochemical, and molecular analyses. Lipid droplet area, inflammatory infiltration, and collagen deposition were evaluated on tissue sections; total lipid content and oxidative stress markers were assessed in homogenates and isolated mitochondria. Molecular pathways related to oxidative stress, lipid metabolism, and fibrosis were assessed at protein and mRNA levels.
Results:
CIM treatment significantly reduced oxidative stress (ROS, lipid peroxidation, nitrogen species), promoting AMPK activation and metabolic reprogramming. This included increased expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its target genes, and decreased sterol regulatory element binding protein-1c (SREBP-1c)-driven lipogenesis. These changes halted fibrosis progression, as confirmed by Picro-Sirius Red staining and fibrosis markers.
Conclusions:
these findings indicate that Complex I modulation may represent a promising strategy to counteract MASLD progression toward MASH.
Insights
A novel Complex I Modulator (CIM) reduced oxidative stress and inflammation in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). This therapeutic approach may offer a promising strategy for treating MASH progression.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Pharmacology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) involves mitochondrial dysfunction, oxidative stress, and inflammation, driving progression to MASH and HCC.
- Mitochondrial Complex I is a key source of reactive oxygen species (ROS), particularly in dysregulated metabolism.
- Metformin's Complex I inhibition reduces ROS and activates AMPK, suggesting similar modulators could be therapeutic.
Purpose of the Study:
- To evaluate a novel Complex I Modulator (CIM, BI4500) for its potential to reduce oxidative stress, inflammation, lipid accumulation, and fibrosis in a rat model of MASH.
- To investigate CIM's effects on mitochondrial function, metabolic reprogramming, and key molecular pathways involved in MASH pathogenesis.
Main Methods:
- Rats were fed a methionine- and choline-deficient (MCD) diet for six weeks, with CIM or vehicle treatment initiated at week four.
- Liver tissues underwent histological, biochemical, and molecular analyses to assess lipid droplets, inflammation, collagen, oxidative stress markers, and gene/protein expression.
- Key pathways evaluated included oxidative stress, lipid metabolism (PPAR-α, SREBP-1c), and fibrosis markers.
Main Results:
- CIM treatment significantly decreased oxidative stress markers (ROS, lipid peroxidation, nitrogen species) and promoted AMPK activation.
- Metabolic reprogramming occurred, characterized by increased PPAR-α pathway activity and decreased SREBP-1c-driven lipogenesis.
- Fibrosis progression was halted, evidenced by reduced collagen deposition and fibrosis markers.
Conclusions:
- Complex I modulation with CIM effectively attenuated key pathological features of MASH in a preclinical model.
- CIM demonstrated potential to counteract MASLD progression by addressing mitochondrial dysfunction, oxidative stress, and inflammation.
- Targeting Mitochondrial Complex I represents a promising therapeutic strategy for MASLD and MASH.
Related Concept Videos
01:24Overview of Lipid Metabolism
Lipolysis: The Breakdown of Lipids:
Lipolysis is the process of breaking down lipids, particularly triglycerides, into glycerol and fatty acids. This process typically occurs in the adipose tissue and is triggered by various hormones, including glucagon and...
01:26Redox Titration: Other Oxidizing and Reducing Agents
02:45Responses to Heat and Cold Stress
00:52What is Metabolism?
03:14Oxidation Numbers
01:15Pyruvate Oxidation
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...