1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway

Metabolic-dysfunction associated hepatic steatotic liver disease (MASLD) plays a major role in the pathogenesis of type 2 diabetes and can lead to end stage liver disease but there are currently no FDA approved treatments. CIDEB deficiency has been shown to be associated with reduced incidence of MASLD in humans however the mechanism by which it does so remains unknown. We found that knocking down hepatic expression of CIDEB using an antisense oligonucleotide decreased hepatic triglyceride accumulation by ~150% (p = 0.0001) in high fat fed (HFD) mice. This reduction in hepatic fat content could be mostly attributed to a ∼30% increase rates of hepatic mitochondrial fat oxidation as assessed by a novel [¹³C₅]glutamine tracer infusion technique (Q-Flux). In order to assess the impact of reduced hepatic steatosis on hepatic and whole-body insulin sensitivity we performed hyperinsulinemic-euglycemic clamp studies. CIDEB knockdown ameliorated HFD-induced insulin resistance in mice, reflected by ∼2-fold (p = 0.001) increase in the glucose infusion rate required to maintain euglycemia. These improvements in hepatic insulin sensitivity were associated with decreased plasma membrane (PM)/cytosol PKCε translocation and increased insulin-stimulated phosphorylation of IRK^Y1158, IRK^Y1162, Akt^S473 and Akt^T308 (all p < 0.05).

Conclusion: These results demonstrate that CIDEB knockdown increases mitochondrial fat oxidation and ameliorates HFD-induced hepatic steatosis and hepatic insulin resistance through the PKCε-insulin receptor kinase pathway and suggest that CIDEB knockdown may represent a novel therapeutic approach to treat MASLD.