MON-576 The Role of Hepatic PKCε in Insulin Resistance and Sensitivity Under High- Fructose Diet Conditions

Abstract Disclosure: T. Harris: None. M.A. Rahman: None. S. Andrisse: None. Excessive intake of high-fat (HFD) and high-fructose (HFrD) diets contributes to liver fat accumulation, insulin resistance, and metabolic disorders. Liver protein kinase Cε (PKCε) has been linked to these issues, particularly in insulin resistance, though the molecular mechanisms underlying its role remain to be fully elucidated. This study looks at how PKCε affects insulin signaling and resistance in high-fructose diet (HFrD) conditions using liver-specific PKCε heterozygous (PKCε-het) mice. We hypothesized that PKCε-het mice on a HFrD would exhibit enhanced insulin stimulation compared to PKCε-het mice on a control diet. PKCε-het and control mice were fed either a control (D12450J) or high-fructose diet (D02022704) for two months (Research Diets Inc., RDI). We measured p-AKT2, PEPCK, IRS1, and IRS2 protein levels using Western blot under both basal and insulin-stimulated conditions. Fold induction data from p-AKT2 analysis demonstrated a 3-fold increase in insulin-stimulated p-AKT2 levels in PKCε-het HFrD mice compared to controls, supporting enhanced insulin sensitivity. Similarly, IRS-1 analysis revealed a 2-fold induction in insulin-stimulated IRS-1 levels in PKCε-het mice, and IRS-2 analysis demonstrated a significant 20-fold (basal) and 40-fold (insulin stimulated) increase in IRS-2 levels in PKCε-het mice compared to controls, further supporting improved insulin signaling. Interestingly, PEPCK analysis showed a 20-fold reduction in PEPCK expression in PKCε-het mice under insulin-stimulated conditions, indicating improved suppression of gluconeogenesis. These results highlight the potential of targeting hepatic PKCε as a novel therapeutic approach to mitigate the adverse metabolic effects of high-fructose and high-fat diets. The enhanced insulin sensitivity observed in PKCε-het mice, evidenced by increased activation of p-AKT2, IRS-1, and IRS-2, along with the significant suppression of PEPCK expression, suggests that reducing PKCε expression improves hepatic insulin response and glucose metabolism. These results provide further insight into the molecular mechanisms linking PKCε to insulin resistance and metabolic dysfunction. Targeting PKCε may offer a potential therapeutic strategy for mitigating insulin resistance and related metabolic disorders Presentation: Monday, July 14, 2025