Angiopoietin-like 4: a decade of research
Zhu, P. ; Goh, Y.Y. ; Chin, H.F.A. ; Kersten, A.H. ; Tan, N.S. - \ 2012
Bioscience Reports 32 (2012)3. - ISSN 0144-8463 - p. 211 - 219.
induced adipose factor - fatty-acids - tgf-beta - anoikis resistance - lipoprotein-lipase - human adipocytes - target gene - protein - angptl4 - expression
The past decade has seen a rapid development and increasing recognition of ANGPTL4 (angiopoietin-like 4) as a remarkably multifaceted protein that is involved in many metabolic and non-metabolic conditions. ANGPTL4 has been recognised as a central player in various aspects of energy homoeostasis, at least in part, via the inhibitory interaction between the coiled-coil domain of ANGPTL4 and LPL (lipoprotein lipase). The fibrinogen-like domain of ANGPTL4 interacts and activates specific integrins to facilitate wound healing, modulates vascular permeability, and regulates ROS (reactive oxygen species) level to promote tumorigenesis. The present review summarizes these landmark findings about ANGPTL4 and highlights several important implications for future clinical practice. Importantly, these implications have also raised many questions that are in urgent need of further investigations, particularly the transcription regulation of ANGPTL4 expression, and the post-translation cleavage and modifications of ANGPTL4. The research findings over the past decade have laid the foundation for a better mechanistic understanding of the new scientific discoveries on the diverse roles of ANGPTL4.
Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury
Li, Shenyang ; Nagothu, K. ; Ranganathan, G. ; Ali, S.M. ; Shank, B. ; Gokden, N. ; Ayyadevara, S. ; Megysi, J. ; Olivecrona, G. ; Chugh, S.S. ; Kersten, A.H. ; Portilla, D. - \ 2012
American Journal of Physiology : Renal Physiology 303 (2012)3. - ISSN 1931-857X - p. F437 - F448.
adipose-tissue - human adipocytes - ppar-alpha - induced nephrotoxicity - density-lipoprotein - failure - metabolism - expression - mechanisms - deficiency
Peroxisome proliferator-activated receptor-a (PPARa) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARa and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity. CP also reduced kidney LPL expression and activity. Angptl4 mRNA levels were increased by ninefold in liver and kidney tissue and by twofold in adipose tissue of CP-treated mice. Western blots of two-dimensional gel electrophoresis identified increased expression of a neutral pI Angptl4 protein in kidney tissue of CP-treated mice. Immunolocalization studies showed reduced staining of LPL and increased staining of Angptl4 primarily in proximal tubules of CP-treated mice. CP also increased TG accumulation in kidney tissue, which was ameliorated by PPARa ligand. In summary, a PPARa ligand ameliorates CP-mediated nephrotoxicity by increasing LPL activity via increased expression of GPHBP1 and Lmf1 and by reducing expression of Angptl4 protein in the proximal tubule.
The Inflammasome and Caspase-1 Activation: A New Mechanism Underlying Increased Inflammatory Activity in Human Visceral Adipose Tissue
Koenen, T.B. ; Stienstra, R. ; Tits, L.J. van; Joosten, L.A.B. ; Velzen, J.F. ; Hijmans, A. ; Pol, J.A. ; Vliet, J.A. van der; Netea, M.G. ; Tack, C.J. ; Stalenhoef, A.F.H. ; Graaf, J. de - \ 2011
Endocrinology 152 (2011)10. - ISSN 0013-7227 - p. 3769 - 3778.
necrosis-factor-alpha - insulin-resistance - nalp3 inflammasome - metabolic syndrome - abdominal obesity - human adipocytes - crucial role - interleukin-1-beta - plasma - macrophages
The immune competent abdominal adipose tissue, either stored viscerally [visceral adipose tissue (VAT)] or sc [sc adipose tissue (SAT)], has been identified as a source of IL-1 beta and IL-18. To become active, the proforms of these cytokines require processing by caspase-1, which itself is mediated by the inflammasome. In this descriptive study, we investigate the expression of inflammasome components and caspase-1 in human fat and determine whether caspase-1 activity contributes to the enhanced inflammatory status of VAT. Paired SAT and VAT biopsies from 10 overweight subjects (body mass index, 25-28 kg/m(2)) were used to study the cellular composition and the intrinsic inflammatory capacity of both adipose tissue depots. The percentage of CD8(+) T cells within the lymphocyte fraction was significantly higher in VAT compared with SAT (41.6 vs. 30.4%; P <0.05). Adipose tissue cultures showed a higher release of IL-1 beta (10-fold; P <0.05), IL-18 (3-fold; P <0.05), and IL-6 and IL-8 (3-fold, P <0.05; and 4-fold, P <0.05, respectively) from VAT compared with SAT that was significantly reduced by inhibiting caspase-1 activity. In addition, caspase-1 activity was 3-fold (P <0.05) higher in VAT compared with SAT, together with an increase in the protein levels of the inflammasome members apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain (2-fold; P <0.05) and nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (2-fold; nonsignificant). Finally, caspase-1 activity levels were positively correlated with the percentage of CD8(+) T cells present in adipose tissue. Our results show that caspase-1 and nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 inflammasome members are abundantly present in human VAT. The increased intrinsic caspase-1 activity in VAT represents a novel and specific inflammatory pathway that may determine the proinflammatory character of this specific depot. (Endocrinology 152: 3769-3778, 2011)
PPARy activity in subcutaneous abdominal fat tissue and fat mass gain during short-term overfeeding
Joosen, A.M.C.P. ; Bakker, A.H.F. ; Zorenc, A.H.G. ; Kersten, A.H. ; Schrauwen, P. ; Westerterp, K.R. - \ 2006
International Journal of Obesity 30 (2006)2. - ISSN 0307-0565 - p. 302 - 307.
activated receptor-gamma - gene-expression - transcriptional regulation - human adipocytes - adipose-tissue - in-vivo - insulin - adipogenesis - obesity - alpha
Objective: As the peroxisome proliferator-activated receptor (PPAR) plays a central role in fat mass regulation, we investigated whether initial subcutaneous PPAR activity is related to fat mass generation during overfeeding. Subjects: Fourteen healthy female subjects (age 254 years, BMI 22.12.3 kg/m2). Design and measurements: Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Fasting blood samples were analyzed for leptin, insulin and glucose. Fasting subcutaneous abdominal fat biopsies were obtained for analysis of PPAR1, PPAR2, aP2 and UCP2 mRNAs. Results: Initial PPAR1 and 2, aP2 and UCP2 mRNAs were not related to fat gain (P>0.12). However, PPAR1, PPAR2 and aP2 mRNA changes were positively related to changes in plasma leptin (P