Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice

Abstract

The nuclear liver X receptor (LXR) regulates multiple aspects of cholesterol, triacylglycerol (TG), and carbohydrate metabolism. Activation of LXR induces the expression of genes encoding enzymes involved in de novo lipogenesis (DNL) resulting in hepatic steatosis in mice. Pharmacological LXR activation has also been reported to improve insulin sensitivity and glucose homeostasis in diabetic rodents. The effects of pharmacological LXR ligands on insulinʼs action on hepatic lipid metabolism are not known. We evaluated secretion of VLDL during a hyperinsulinemic euglycemic clamp in mice treated with the LXRligand T0901317. In untreated mice, hyperinsulinemia reduced the availability of plasma NEFA for VLDL-TG synthesis, increased the contribution of DNL to VLDL-TG, reduced VLDL particle size, and suppressed overall VLDL-TG production rate by approximately 50%. Upon T0901317 treatment, hyperinsulinemia failed to reduce VLDL particle size or suppress VLDL-TG production rate, but the contribution of DNL to VLDL-TG was increased. In conclusion, the effects of LXR activation by T0901317 on lipid metabolism can override the normal control of insulin to suppress VLDL particle secretion.-Grefhorst, A., and E. J. Parks. Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice.

Serum TG-lowering properties of plant sterols and stanols are associated with decreased hepatic VLDL secretion

“…Hepatic VLDL secretion and de novo lipogenesis have been reported to be regulated by several transcription factors including liver X receptor (LXR) ( 17,(21)(22)(23). To study whether PSE and PSA feeding may infl uence VLDL secretion via downregulation of LXR signaling, we determined expression levels of LXR target genes.…”

Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance

“…LXRs integrate lipid and inflammatory signaling pathways in both the innate and adaptive immune systems (Bensinger et al, 2008; Hong et al, 2012; Joseph et al, 2004; Joseph et al, 2003; N et al, 2009; Zelcer and Tontonoz, 2006). Ligand activation of LXRs promotes cholesterol excretion (Peet et al, 1998; Schultz et al, 2000; Tontonoz and Mangelsdorf, 2003) and reduces inflammation, but simultaneously stimulates de novo lipogenesis of triglycerides (Repa et al, 2000a; Repa et al, 2000b; Schultz et al, 2000), a potentially deleterious effect contributing to hepatic steatosis and possibly hepatic insulin resistance (Grefhorst and Parks, 2009). …”

Parameter Trajectory Analysis to Identify Treatment Effects of Pharmacological Interventions

“…Formulating mathematical descriptions of these effects is furthermore complicated by the lack of sufficient information of the underlying network structure and interaction mechanisms. An example is the study of pharmacological treatments associated with metabolic diseases [20], [21]. The acquired experimental data predominantly concern changes in plasma and tissue metabolite concentrations during one or more stages of the treatment.…”