Nonalcoholic fatty liver disease (NAFLD) and its evolution to inflammatory steatohepatitis (NASH) are the most common causes of chronic liver damage and transplantation that are reaching epidemic proportions due to the upraising incidence of metabolic syndrome, obesity, and diabetes. Currently, there is no approved treatment for NASH. The mitochondrial citrate carrier, Slc25a1, has been proposed to play an important role in lipid metabolism, suggesting a potential role for this protein in the pathogenesis of this disease. Here, we show that Slc25a1 inhibition with a specific inhibitor compound, CTPI-2, halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, while starkly mitigating obesity induced by a high-fat diet. These effects are differentially recapitulated by a global ablation of one copy of the Slc25a1 gene or by a liver-targeted Slc25a1 knockout, which unravel dose-dependent and tissue-specific functions of this protein. Mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts signaling from peroxisome proliferator-activated receptor gamma, a key regulator of glucose and lipid metabolism, and inhibits the expression of gluconeogenic genes. The combination of these activities leads not only to inhibition of lipid anabolic processes, but also to a normalization of hyperglycemia and glucose intolerance as well. In summary, our data show for the first time that Slc25a1 serves as an important player in the pathogenesis of fatty liver disease and thus, provides a potentially exploitable and novel therapeutic target.

The mitochondrial citrate/isocitrate carrier, CIC, has been shown to play an important role in a growing list of human diseases. CIC belongs to a large family of nuclear-encoded mitochondrial transporters that serve the fundamental function of allowing the transit of ions and metabolites through the impermeable mitochondrial membrane. Citrate is central to mitochondrial metabolism and respiration and plays fundamental activities in the cytosol, serving as a metabolic substrate, an allosteric enzymatic regulator and, as the source of Acetyl-Coenzyme A, also as an epigenetic modifier. In this review, we highlight the complexity of the mechanisms of action of this transporter, describing its involvement in human diseases and the therapeutic opportunities for targeting its activity in several pathological conditions.

No abstract

Biallelic germline mutations in the SLC25A1 gene lead to combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a devastating and fatal systemic disease uniquely characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). How SLC25A1 deficiency contributes to D/L-2HGA and the role played by 2HG is unclear and, consequently, no therapy exists. Both enantiomers are proposed to act as oncometabolites, but their activities in normal tissues remain understudied. Here we show that mice lacking both SLC25A1 alleles exhibit developmental abnormalities that mirror human D/L-2HGA. SLC25A1 deficient cells isolated from SLC25A1-/- mice undergo premature mitochondrial dysfunction associated senescence, indicating that loss of proliferative capacity underlies the pathogenesis of D/L-2HGA. Remarkably, D- and L-2HG directly induce mitochondrial respiratory dysfunction and treatment of zebrafish embryos with the combination of D- and L-2HG phenocopies SLC25A1 loss, inducing developmental abnormalities in an additive fashion relative to either enantiomer alone. Subsequent metabolic analysis demonstrated that glutamine acts as a precursor for 2HG synthesis and SLC25A1 deficient tissues and cells from D/L-2HGA patients undergo global remodeling towards glutamine metabolism. Therefore, we explored the pre-clinical relevance of phenylbutyrate, an FDA-approved drug that reduces the blood glutamine levels and we found that it reduces 2HG accumulation reversing metabolic abnormalities in patients affected by D/L-2HGA. These results reveal pathogenic and growth suppressive activities of D- and L-2HG in the context of SLC25A1 deficiency and expose metabolic vulnerabilities for the clinical management of this disease.

INTRODUCTION Endothelial progenitor cells (EPCs) in non transplant settings have reparative properties. However, their role in heart transplantation (HT) is not well defined. OBJECTIVES The aim of this study was to prospectively evaluate changes in EPC levels in relation to post-HT rejection. PATIENTS AND METHODS EPC levels were measured in 27 HT recipients for 6 months after HT. Acute cellular rejection (ACR) or antibody-mediated rejection (AMR) were assessed by right ventricular endomyocardial biopsy. RESULTS ACR and AMR were observed in 7 (25.9%) and 6 (22.2%) patients, respectively. The ACR status at 1 month post-HT did not differ with respect to EPC immediately post-HT. At 1 month post-HT in patients without ACR or AMR, EPC levels were significantly reduced compared with the measurements immediately post-HT (P <0.001). On further follow-up, EPC levels were similar regardless of the rejection events. Nonetheless, greater changes (coefficient of variation) in EPClog (logarithmic transformation) were associated with the risk of AMR or ACR compared with those without any rejection event (median [lower-upper quartile], 15 [13-18] vs 8 [5-13]; P = 0.02 and 22 [14-26] vs 8 [5-13]; P = 0.01, respectively). The receiver operating characteristic curve showed that the coefficient of variation of EPClog of 12 was the optimal cutoff value for the prediction of rejection (area under the curve = 0.85). Higher levels were associated with greater risk of ACR or AMR (P <0.005). CONCLUSIONS Early reduction of EPC levels was related to a lower risk of ACR or AMR. Greater changes of EPC-levels during follow-up were associated with a significantly higher risk of rejection.