Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis.
Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion.
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Key Laboratory of Medical Electrophysiology, Ministry of Education of China, China; Institute of Cardiovascular Research, Sichuan Medical University, Luzhou 646000, China.
Yinyuan
Y
Ding
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: xunde.xian@utsouthwestern.edu.
Xunde
X
Xian
Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
William L
WL
Holland
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA; Dallas VA Medical Center, Dallas, TX 75216, USA.
Shirling
S
Tsai
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: joachim.herz@utsouthwestern.edu.
Joachim
J
Herz
D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D051273:Glucose Transporter Type 2; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D011972:Receptor, Insulin
Chylomicron remnant; Diabetes; Insulin resistance; Insulin, metabolic syndrome; LRP1; Lipoprotein; PDGF