An intimate collaboration between peroxisomes and lipid bodies

Although peroxisomes oxidize lipids, the metabolism of lipid bodies and peroxisomes is thought to be largely uncoupled from one another. In this study, using oleic acid–cultured Saccharomyces cerevisiae as a model system, we provide evidence that lipid bodies and peroxisomes have a close physiological relationship. Peroxisomes adhere stably to lipid bodies, and they can even extend processes into lipid body cores. Biochemical experiments and proteomic analysis of the purified lipid bodies suggest that these processes are limited to enzymes of fatty acid β oxidation. Peroxisomes that are unable to oxidize fatty acids promote novel structures within lipid bodies (“gnarls”), which may be organized arrays of accumulated free fatty acids. However, gnarls are suppressed, and fatty acids are not accumulated in the absence of peroxisomal membranes. Our results suggest that the extensive physical contact between peroxisomes and lipid bodies promotes the coupling of lipolysis within lipid bodies with peroxisomal fatty acid oxidation

LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome

BACKGROUND: The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. METHODS AND PRINCIPAL FINDINGS: We show that loss of LRP1 in VSMC (smLRP(−)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1(−) animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels. CONCLUSIONS AND SIGNIFICANCE: Our findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity

A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity

The acute depletion of membrane cholesterol causes the concentration of pERK1/2 in caveola/raft lipid domains and the cytosol of human fibroblasts to dramatically increase. This increase could be caused by either the activation of MEK-1 or the inhibition of a pERK phosphatase. Here we describe the isolation of a high molecular weight (∼440 kDa), cholesterol-regulated pERK phosphatase that dephosphorylates both the phosphotyrosine and the phosphothreonine residues in the activation loop of the enzyme. The dual activity in the complex appears to be due to the combined activities of the serine/threonine phosphatase PP2A and the tyrosine phosphatase HePTP. Acute depletion of cholesterol causes the disassembly of the complex and a concomitant loss of the dual specificity pERK phosphatase activity. The existence of a cholesterol-regulated HePTP/PP2A activity provides a molecular explanation for why ERK activity is sensitive to membrane cholesterol levels, and raises the possibility that ERK plays a role in regulating the traffic of cholesterol to caveolae/rafts and other membranes

Activation of TGFβ and PDGF signaling in LRP⁻ mouse aortas are both prevented upon rosiglitazone treatment.

<p>Mice had been cholesterol-fed for 5 weeks in the absence (−Rosi) or presence (+Rosi) of rosiglitazone (GlaxoSmithKline, 25 mg/kg/day) before analysis. Mouse aortas expressing (LRP⁺) or not expressing (LRP⁻) LRP in VSMC were analyzed by western blot (Panel A) and immunohistochemistry (Panel B) for expression of PDGFRβ (d–f), and for activation of Smad2/3 (pSmad2/3, a–c), and Erk1/2 (pErk1/2, g–i). Panel C shows elastic staining of corresponding sections and gaps in elastic fiber continuity (arrows). Bar indicates 40 µm, insert scale bar in B,a indicates 10 µm.</p

Increased pSmad2/3 expression and activation of TGFβ signaling in LRP⁻ mouse aorta.

<p>Longitudinal sections of abdominal aorta from SM22Cre⁺;LRP^flox/flox;LDLR^−/− (LRP⁻) and LRP^flox/flox;LDLR^−/− (LRP⁺) mice were stained with anti-TSP1, anti-TGFβ1, anti-pSmad2/3 and anti-pSmad1 antibodies. Reduced LRP1 expression results in greatly enhanced expression of pSmad2/3 and its target gene, TSP1. By contrast, TGFβ1 levels were slightly reduced, pSmad1 levels did not change. Bar in a indicates 20 µm.</p