Inhibition of mitochondrial citrate shuttle alleviates metabolic syndromes induced by high-fat diet
The mitochondrial citrate shuttle, which depends on the solute carrier family 25 member 1 (SLC25A1), is crucial for transferring citrate from the mitochondria to the cytoplasm. This process supports glycolysis, lipid synthesis, and protein acetylation. While much research has focused on SLC25A1 in pathological contexts, especially in high-fat diet (HFD)-induced obesity, the effects of SLC25A1 inhibition on nutrient metabolism under HFD conditions are not well understood. To address this, we used zebrafish (Danio rerio) and Nile tilapia (Oreochromis niloticus) to investigate the impact of inhibiting Slc25a1.
In zebrafish, we applied Slc25a1-specific inhibitors (CTPI-2) for 4 weeks, while Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibiting the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance, with glucose tolerance remaining unaffected. Slc25a1 inhibition altered hepatic protein acetylation, decreasing cytoplasmic acetylation and increasing mitochondrial acetylation. Under HFD conditions, this inhibition enhanced fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). Additionally, the inhibition caused acetylation-induced inactivation of Pdhe1α, leading to decreased glucose oxidative catabolism and increased glucose uptake and storage in zebrafish livers.
Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and boosting oxidative phosphorylation for energy production. These findings shed light on the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD.
NEW & NOTEWORTHY: The mitochondrial citrate shuttle is essential for metabolic balance. Our study shows that inhibiting Slc25a1, a key component of this shuttle, can mitigate metabolic disorders induced by a high-fat diet by remodeling hepatic protein acetylation. Specifically, Slc25a1 inhibition reduces liver triglyceride accumulation by deacetylating Cpt1a and decreases glucose oxidative catabolism by acetylating Pdhe1α. These insights offer new perspectives on treating diet-induced metabolic disorders.