AI Insight
This study demonstrates that copper deficiency contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and that liver-targeted copper supplementation can reduce abnormal lipid accumulation in the liver. The researchers found that copper activates lipolysis of lipid droplets by inhibiting the enzyme PDE3B, which in turn activates PKA signaling and downstream targets HSL and AMPK. The fatty acids released through this process are then broken down via mitochondrial fatty acid oxidation, supported by increased activity of copper-dependent respiratory complex IV and SOD1.
Why it matters
MASLD affects a large proportion of the global population and currently lacks approved pharmacological treatments, making this copper-based therapeutic approach a potentially meaningful new direction. If validated in clinical settings, liver-targeted copper supplementation could offer a novel and relatively accessible metabolic intervention for patients with fatty liver disease.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Abstract: Metabolic-associated steatotic liver disease (MASLD) is a prevalent liver disease driven by complex dysregulation of hepatic lipid metabolism. Here we show that copper deficiency is a nutrient vulnerability in steatotic liver disease and that selective liver-targeted copper supplementation can reduce excess lipid accumulation. Analysis of steatotic patient and mouse tissues identify widespread alterations in hepatic copper homeostasis markers. Integrated multi-omics analyses reveal that copper induces lipolysis of PLIN2-containing lipid droplets while lipid importer CD36 is downregulated. We show that copper inhibits cAMP hydrolase activity of PDE3B, thus activating PKA-mediated HSL and AMPK activation upstream of lipolysis. Fatty acids liberated through lipolysis are subsequently degraded via enhanced mitochondrial fatty acid oxidation, supported by energetic rewiring toward oxidative phosphorylation (OXPHOS) with increased copper-dependent complex IV and SOD1 activity. Our findings establish a multi-pronged mechanism by which hepatic copper supplementation coordinately regulates lipid metabolism in response to steatosis and unveils a therapeutic metallomedicine strategy to rewire lipid regulation.