Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) and inflammatory steatohepatitis (NASH) comprise a spectrum ofThese authors contributed : Mingjun Tan, Rami Mosaoa Edited by C
To assess whether Slc25a1 is relevant to NAFLD/NASH, we performed IHC analysis of human tissue microarrays derived from the liver of patients with NASH, which showed higher expression levels relative to normal livers (Fig. 1b, top panels; quantified in Fig. 1c and Supplementary Fig. S1)
Magnetic resonance imaging (MRI) performed in animals enrolled in the reversion study, as well as visual examination of their abdomen confirmed that CTPI-2 reduced the white visceral abdominal fat (WAT) (Fig. 1i, j)
Summary
Nonalcoholic fatty liver disease (NAFLD) and inflammatory steatohepatitis (NASH) comprise a spectrum of. These authors contributed : Mingjun Tan, Rami Mosaoa Edited by C. With the development of effective therapeutics for hepatitis C, NAFDL/NASH is predicted to become the most common cause of chronic liver disease and transplantation with a worldwide prevalence as high as 25%. Fatty liver disease can be corrected with dietetic adjustments, while at later stages several agents have been proposed as effective. Given the role of altered lipid metabolism and the deleterious effects of lipotoxicity, inhibitors of the lipid synthetic pathway, including inhibitors of fatty acid synthase (FASN) or acetyl-coenzyme-A carboxylase, ACC1/2, are being explored as potential therapeutics. The development of NASH therapeutics represents an unmet clinical need, to the point that the Food and Drug Administration has recently emphasized the necessity to identify new therapies that slow or reverse the progression of NAFLD/NASH
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