INNOVATION:   The liver X receptors (LXRα and LXRβ) are nuclear receptors activated by oxysterols that are recognized to play an important role in the control of lipid homeostasis. Recent work in the laboratory of Dr. Peter Tontonoz has demonstrated a previously unrecognized role for LXRs in the control of glucose metabolism in liver and adipose tissue. LXR agonists were shown to improve glucose tolerance and enhance the expression of the insulin-sensitive glucose transporter, GLUT 4, in adipose tissue. In addition, LXR agonists were observed to suppress genes involved in gluconeogenesis and induction of hepatic glucokinase expression. Together, these effects in adipose tissue and liver would be expected to promote peripheral glucose uptake and limit hepatic glucose production.

ADVANTAGES:   A previously unknown signaling pathway for the modulation of glucose metabolism may now be exploited to develop novel pharmacological agents to treat type II diabetes, obesity, insulin resistance and related disorders.

APPLICATIONS:   Novel pharmaceutical compounds for the treatment of type II diabetes, insulin resistance, obesity and related disorders may be developed that act via LXRs in specific tissues to modulate genes involved in glucose transport (eg, GLUT4) and gluconeogenesis. Adipose expression of GLUT4 is an important determinant of insulin sensitivity. Pharmaceutical compounds may now be developed that act via LXRs in adipose tissue to activate GLUT4 to enhance insulin sensitivity and glucose uptake. In another application, pharmaceutical compounds may be developed that act via LXRs to specifically suppress hepatic glucose production. Either approach to improved glucose tolerance would be expected to ameliorate the symptoms of diseases associated with impaired insulin sensitivity.

DEVELOPMENT TO DATE:   UCLA investigators demonstrated that the synthetic LXR agonist GW3965 improved glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Gene expression analysis revealed that LXR agonist induced expression of GLUT4 in adipose tissue via direct action of the LXR/retinoid X receptor heterodimer on the GLUT4 promoter. Consistent with their effects on GLUT4 expression, LXR agonists promoted uptake in 3T3-L1 adipocytes in vitro. Activation of LXR also led to the suppression of gluconeogenesis in the liver by (a) down-regulation of genes involved in gluconeogenesis [eg, phoshpoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1), and glucose-6-phosphatase], and (b) induction of hepatic glucokinase expression, which promotes hepatic glucose utilization. These results reveal coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue.

Related Papers (Selected) Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl. Acad. Sci. USA. 2003; 9, 5419-5424. more...

Reference: UCLA Case No. 2003-189

PCT Application: PCT/US03/40906