A Liver-Targeted Copper Supplement Reduces Metabolic Dysfunction-Associated Liver Steatosis by Increasing Lipolysis and Fatty Acid Oxidation

Summary

This research identifies copper deficiency as a nutrient vulnerability in metabolic dysfunction-associated steatotic liver disease and demonstrates that selective liver-targeted copper supplementation reduces hepatic lipid accumulation through coordinated activation of lipolysis and mitochondrial fatty acid oxidation. Multi-omics analyses of patient and mouse tissues reveal that copper inhibits the cAMP hydrolase activity of PDE3B, triggering PKA and AMPK-mediated lipolysis of PLIN2-containing lipid droplets, whilst concurrently downregulating the lipid importer CD36. The mechanism is supported by energetic rewiring toward oxidative phosphorylation via increased copper-dependent enzymatic activities, suggesting a therapeutic metallomedicine strategy for lipid regulation in steatotic liver disease.

Regional applicability

This laboratory and mechanistic study does not describe a field intervention or farming system outcome; it is a basic research investigation of copper supplementation mechanisms in human liver disease. Whilst copper nutrition and soil micronutrient status are relevant to UK agricultural policy, the findings are translational rather than directly applicable to UK farming or land management practice, though they may inform future dietary recommendations or nutraceutical development.

Key measures

Hepatic copper homeostasis markers, lipid droplet dynamics (PLIN2), lipid importer expression (CD36), lipolysis markers (HSL, AMPK), mitochondrial fatty acid oxidation, oxidative phosphorylation (OXPHOS) activity, copper-dependent enzyme activity (complex IV, SOD1)

Outcomes reported

The study examined whether copper deficiency contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and whether liver-targeted copper supplementation reduces hepatic lipid accumulation. The research identified mechanisms by which copper enhances lipolysis and fatty acid oxidation through multi-omics analysis of patient and mouse tissues.

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