Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia

Background and aims

Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.

Methods

ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.

Results

Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.

Conclusion

Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.