Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation
| Autor: | Ronald M. Krauss, Ba-Bie Teng, Yuanyuan Qin, Rosanne M. Crooke, Andréa C. Dosé, Zemin Yao, Jacob Strelnikov, Mohsen Amir Alipour, Marisa W. Medina, Mee J. Kim, Joseph Harmon, Feng Gao, Flora Ting |
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| Rok vydání: | 2020 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate Male phosphatidylinositol Vesicular Transport Proteins Cardiorespiratory Medicine and Haematology Inbred C57BL chemistry.chemical_compound Receptors 2.1 Biological and endogenous factors Aetiology Receptor Mice Knockout Liver Disease lipoprotein Hep G2 Cells Transmembrane protein Phosphatidylinositol 4 Protein Transport Cholesterol Phosphatidylinositol 4 5-bisphosphate Biochemistry Liver 5-Diphosphate lysosome lipids (amino acids peptides and proteins) Female Phosphoinositide Phosphatases Cardiology and Cardiovascular Medicine mice 1.1 Normal biological development and functioning Knockout Phosphatase Clinical Sciences Down-Regulation Diet High-Fat Article LDL Underpinning research Pi Animals Humans Nutrition cholesterol Atherosclerosis Diet Mice Inbred C57BL High-Fat chemistry Receptors LDL Cardiovascular System & Hematology LDL receptor Proteolysis Hepatocytes Degradation (geology) Digestive Diseases Lysosomes Lipoprotein |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology, vol 40, iss 5 Arterioscler Thromb Vasc Biol |
| Popis: | Objective: TMEM55B (transmembrane protein 55B) is a phosphatidylinositol-(4,5)-bisphosphate (PI[4,5]P 2 ) phosphatase that regulates cellular cholesterol, modulates LDLR (low-density lipoprotein receptor) decay, and lysosome function. We tested the effects of Tmem55b knockdown on plasma lipids in mice and assessed the roles of LDLR lysosomal degradation and change in (PI[4,5]P 2 ) in mediating these effects. Approach and Results: Western diet–fed C57BL/6J mice were treated with antisense oligonucleotides against Tmem55b or a nontargeting control for 3 to 4 weeks. Hepatic Tmem55b transcript and protein levels were reduced by ≈70%, and plasma non-HDL (high-density lipoprotein) cholesterol was increased ≈1.8-fold ( P Tmem55b knockdown had no effect on plasma cholesterol in Ldlr −/− mice. In primary hepatocytes and liver tissues from Tmem55b knockdown mice, there was decreased LDLR protein. In the hepatocytes, there was increased lysosome staining and increased LDLR-lysosome colocalization. Impairment of lysosome function (incubation with NH 4 Cl or knockdown of the lysosomal proteins LAMP1 or RAB7 ) abolished the effect of TMEM55B knockdown on LDLR in HepG2 (human hepatoma) cells. Colocalization of the recycling endosome marker RAB11 (Ras-related protein 11) with LDLR in HepG2 cells was reduced by 50% upon TMEM55B knockdown. Finally, knockdown increased hepatic PI(4,5)P 2 levels in vivo and in HepG2 cells, while TMEM55B overexpression in vitro decreased PI(4,5)P 2 . TMEM55B knockdown decreased, whereas overexpression increased, LDL uptake in HepG2 cells. Notably, the TMEM55B overexpression effect was reversed by incubation with PI(4,5)P 2. Conclusions: These findings indicate a role for TMEM55B in regulating plasma cholesterol levels by affecting PI(4,5)P 2 -mediated LDLR lysosomal degradation. |
| Databáze: | OpenAIRE |
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