A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway

Abstract

The pregnane X receptor (PXR) was isolated as a xenosensor regulating xenobiotic responses. In this study, we show that PXR plays an endobiotic role by impacting lipid homeostasis. Expression of an activated PXR in the livers of transgenic mice resulted in an increased hepatic deposit of triglycerides. This PXR-mediated lipid accumulation was independent of the activation of the lipogenic transcriptional factor SREBP-1c (sterol regulatory element-binding protein 1c) and its primary lipogenic target enzymes, including fatty-acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1). Instead, the lipid accumulation in transgenic mice was associated with an increased expression of the free fatty acid transporter CD36 and several accessory lipogenic enzymes, such as stearoyl-CoA desaturase-1 (SCD-1) and long chain free fatty acid elongase. Studies using transgenic and knock-out mice showed that PXR is both necessary and sufficient for Cd36 activation. Promoter analyses revealed a DR-3-type of PXR-response element in the mouse Cd36 promoter, establishing Cd36 as a direct transcriptional target of PXR. The hepatic lipid accumulation and Cd36 induction were also seen in the hPXR "humanized" mice treated with the hPXR agonist rifampicin. The activation of PXR was also associated with an inhibition of pro-␤-oxidative genes, such as peroxisome proliferatoractivated receptor ␣ (PPAR␣) and thiolase, and an up-regulation of PPAR␥, a positive regulator of CD36. The cross-regulation of CD36 by PXR and PPAR␥ suggests that this fatty acid transporter may function as a common target of orphan nuclear receptors in their regulation of lipid homeostasis.

CD36: Implications in cardiovascular disease

“…More recently, expression has been reported on hepatocytes under certain circumstances (Vosper, et al, 2001,Yu, et al, 2001,Zhou, et al, 2006 and smooth muscle cells (Lim, et al, 2006,de Oliveira Silva, Delbosc, Arais, Monnier, Cristol, & Pares-Herbute, 2006, Kwok, Juan, and Ho, 2006. CD36 plays a role in uptake of apoptotic cells (Savill, Hogg, Ren, and Haslett, 1992), shed photoreceptor outer segments , and modified lipoproteins (Endemann, Stanton, Madden, Bryant, White, & Protter, 1993,Podrez, et al,2000, and in recognition of ligands that trigger an innate immune response, including components of gram positive bacteria cell walls (Hoebe, et al, 2005,Stuart, et al, 2005 (as a co-receptor with Toll Like Receptor (TLR) 2), fibrillar amyloid β (Bamberger, Harris, McDonald, Husemann, & Landreth, 2003,El Khoury, et al, 2003, which is a constituent of Alzheimer plaque, and resembles fibrillar amyloid protein (Medeiros, et al, 2004), that may occur in atherosclerotic plaque.…”

“…In muscle cells, the transcription factor FoxO1, which orchestrates a gene program involved in insulin regulation, impacts CD36 expression, and thus has an important effect on fatty acid uptake by these cells (Bastie, et al, 2005). A recent report has shown that CD36 is a downstream target of the pregnane X receptor in liver, and may be involved in lipid accumulation as a result of activation of this pathway (Zhou, et al, 2006).…”

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

“…Serum insulin levels were analyzed with an insulin radioimmunoassay kit from Millipore (St. Charles, MO). To measure liver lipid content, tissues were homogenized and lipids extracted as previously described (61). Lipids were then dissolved in a mixture of 60 l of tert-butanol and 40 l of Triton X-100/methanol (2:1) mix.…”

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

“…19,20 Triglyceride and cholesterol levels were then measured using the Beckman-Coulter Synchron DxC800 chemistry analyzers (Fullerton, CA, USA) according to the manufacturer's instruction.…”