CS and metabolic dysfunction-associated steatohepatitis: 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.