Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism.
Anja Köster,Y. Bernice Chao,Marian Mosior,Amy M. Ford,Patricia Gonzalez-DeWhitt,John E. Hale,De-Shan Li,Yubin Qiu,Christopher C. Fraser,Derek D. Yang,Josef G. Heuer,S. Richard Jaskunas,Patrick I. Eacho +12 more
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TLDR
Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.Abstract:
Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angptl)3 and Angptl4 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4- and Angptl3-deficient mice as well as transgenic mice overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angptl proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.read more
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Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States
Michael K. Badman,Pavlos Pissios,Adam R. Kennedy,George Koukos,Jeffrey S. Flier,Eleftheria Maratos-Flier +5 more
TL;DR: Induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD, and a physiological role for this hepatic hormone is identified.
Journal ArticleDOI
Lipoprotein lipase: from gene to obesity
Hong Wang,Robert H. Eckel +1 more
TL;DR: Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.
Journal ArticleDOI
From molecular action to physiological outputs: Peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions
TL;DR: The molecular mechanisms through which PPARs regulate transcription are thoroughly addressed with particular emphasis on the latest results on corepressor and coactivator action and how the integration of various intra-cellular signaling pathways allowsPPARs to participate to whole-body homeostasis by mediating regulatory crosstalks between organs.
Journal ArticleDOI
Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.
Kiran Musunuru,James P. Pirruccello,James P. Pirruccello,James P. Pirruccello,Ron Do,Ron Do,Ron Do,Gina M. Peloso,Gina M. Peloso,Candace Guiducci,Carrie Sougnez,Kiran V. Garimella,Sheila Fisher,Justin Abreu,Andrew Barry,Timothy Fennell,Eric Banks,Lauren Ambrogio,Kristian Cibulskis,Andrew Kernytsky,Elena Gonzalez,Nicholas Rudzicz,James C. Engert,Mark A. DePristo,Mark J. Daly,Mark J. Daly,Jonathan C. Cohen,Helen H. Hobbs,David Altshuler,David Altshuler,Gustav Schonfeld,Stacey Gabriel,Pin Yue,Sekar Kathiresan,Sekar Kathiresan +34 more
TL;DR: The finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders.
Journal ArticleDOI
Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL
Stefano Romeo,Len A. Pennacchio,Len A. Pennacchio,Yunxin Fu,Eric Boerwinkle,Anne Tybjærg-Hansen,Helen H. Hobbs,Jonathan Cohen +7 more
TL;DR: Analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history in ANGPTL4 in a multiethnic population is reported.
References
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Journal ArticleDOI
Lipoprotein lipase: structure, function, regulation, and role in disease
TL;DR: This review summarises recent findings in relation to the structure, function, and regulation of LPL along with its important role in disease.
Journal ArticleDOI
Characterization of the Fasting-induced Adipose Factor FIAF, a Novel Peroxisome Proliferator-activated Receptor Target Gene
Sander Kersten,Stéphane Mandard,Nguan Soon Tan,Pascal Escher,Daniel Metzger,Pierre Chambon,Frank J. Gonzalez,Béatrice Desvergne,Walter Wahli +8 more
TL;DR: The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions, and is strongly up-regulated by fasting in white adipose tissue and liver.
Journal ArticleDOI
Lipoprotein lipase genetics, lipid uptake, and regulation
TL;DR: Clinical implications of human LPL gene variations, common mutations and their effects on plasma lipids and coronary heart disease are discussed, and the LPL promoter and its regulatory elements are described.
Journal ArticleDOI
Peroxisome Proliferator-Activated Receptor γ Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation
John K. Yoon,Troy Chickering,Evan D. Rosen,Barry J. Dussault,Yubin Qin,Alexander A. Soukas,Jeffrey M. Friedman,William E. Holmes,Bruce M. Spiegelman +8 more
TL;DR: The isolation and characterization of a novel target gene induced by PPARγ ligands, termed PGAR, which encodes a novel member of the angiopoietin family of secreted proteins suggest a possible role for PGAR in the regulation of systemic lipid metabolism or glucose homeostasis.