Targeting Ketohexokinase (KHK) with a Novel Antisense Oligonucleotide (ASO) Decreases De Novo Lipogenesis and Improves Insulin-Mediated Whole Body Glucose Metabolism

Increased sucrose consumption is associated with rising rates of obesity and related conditions [e.g., insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD)]. Ketohexokinase (KHK) catalyzes the first step of fructose metabolism and is highly expressed in liver, kidney and brain, though found in many tissues. Essential fructosuria (hepatic KHK deficiency) is a benign condition, suggesting that KHK is a viable drug target. Inhibition of hepatic KHK would block metabolism of fructose (50% of dietary sucrose) and improve numerous facets of metabolism. ASO’s potently decrease target expression in liver and WAT and we hypothesized that a novel KHK ASO would prevent NAFLD and insulin resistance in normal rats fed a low fat (12% calories from fat), sucrose containing diet (17% calories from fructose). KHK ASO decreased hepatic KHK mRNA and protein expression by 96 and 90%, respectively. KHK ASO decreased WAT mRNA expression by 65%. KHK ASO did not alter body mass. KHK ASO decreased fasting plasma glucose (102±2 vs. 94±2 mg/dL, P=0.01), fasting plasma triglyceride 60% (52±7 vs. 21±2 mg/dL P<0.01) and liver triglyceride by 30% (8.2±0.4 vs. 5.6±0.3 mg TG/g liver, P<0.001) but not plasma insulin or non-esterified fatty acids. Insulin sensitivity was assessed by a 4 mU kg-1 min-1 hyperinsulinemic-euglycemic clamp. Surprisingly, there were no differences in rates of EGP or suppression of EGP. Instead there was a 25% improvement in insulin stimulated whole body glucose metabolism (36.6±0.8 vs. 45.6±2.2, P<0.01). We attribute this to a 40% decrease in hepatic DNL (53±4 vs. 32±4%, P<0.01) and VLDL secretion rate (11.0± 0.8 vs. 5.5± 0.5 mg/dL-min P<0.01) independent of changes in SREBP1 or ChREBP mRNA expression. Thus, decreased DNL and VLDL export prevents fructose induced peripheral insulin resistance. Conclusion: KHK ASO prevents NAFLD, decreases plasma triglyceride and improves insulin sensitivity. Disclosure D. Liu: None. J.A. Sterpka: None. D.F. Vatner: None. M. Bell: Employee; Self; Ionis Pharmaceuticals, Inc.. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. S. Bhanot: Employee; Self; Ionis Pharmaceuticals, Inc.. G. Cline: None. V. Samuel: None.