This chain of events prevents proper FXR-mediated SREBP-1C repression, leading to increases in lipogenesis and overall promotion of the steatotic phenotype of NAFLD/NASH.124,351 Hepatic ceramide exposure has also been found to repress the expression of mitochondrial Citrate Synthase (CS), leading to the accumulation of Acetyl-CoA, the allosteric activator of the first enzyme in gluconeogenesis Pyruvate Carboxylase (PC).132 Hence, hepatic ceramide exposure directly enhances the gluconeogenic and hyperglycemic phenotype associated with T2DM. Here, CS is linked to metabolic dysfunction-associated steatotic liver disease.