Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH

Autor: Erika Parasido, Mingjun Tan, Anna Kasprzyk-Pawelec, Chris Albanese, Rami Mosaoa, Garrett T. Graham, Giuseppe Giaccone, Olga Catalina-Rodriguez, Amrita K. Cheema, Patricia L. Foley, Maria Laura Avantaggiati, Chunling Yi, Bhaskar Kallakury, Shreyas M Gadre
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Blood Glucose
Male
Time Factors
Metabolic disorders
Mice
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease
Fatty liver
Cell Polarity
Fasting
Mitochondria
Phenotype
Liver
030220 oncology & carcinogenesis
Hepatomegaly
medicine.medical_specialty
Down-Regulation
Diet
High-Fat
Article
Citric Acid
03 medical and health sciences
Insulin resistance
Acetyl Coenzyme A
Internal medicine
Glucose Intolerance
medicine
Animals
Humans
Obesity
Fatty acids
Molecular Biology
Triglycerides
Inflammation
business.industry
Interleukin-6
Tumor Necrosis Factor-alpha
Lipogenesis
Macrophages
Gluconeogenesis
Lipid metabolism
Cell Biology
medicine.disease
Transplantation
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
Hyperglycemia
Steatosis
Steatohepatitis
Metabolic syndrome
Insulin Resistance
business
Carrier Proteins
Zdroj: Cell Death and Differentiation
ISSN: 1476-5403
1350-9047
Popis: 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.
Databáze: OpenAIRE
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