Functional Peroxisomes Are Essential for Efficient Cholesterol Sensing and Synthesis

被引:15
|
作者
Charles, Khanichi N. [1 ]
Shackelford, Janis E. [1 ]
Faust, Phyllis L. [2 ]
Fliesler, Steven J. [3 ,4 ,5 ,6 ]
Stangl, Herbert [7 ]
Kovacs, Werner J. [8 ]
机构
[1] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA
[2] Columbia Univ, Vageios Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA
[3] Univ Buffalo State Univ New York SUNY, Dept Ophthalmol, Buffalo, NY USA
[4] Univ Buffalo State Univ New York SUNY, Dept Biochem, Buffalo, NY USA
[5] Univ Buffalo State Univ New York SUNY, Gradate Program Neurosci, Buffalo, NY USA
[6] Vet Adm Western New York Healthcare Syst, Res Serv, Buffalo, NY USA
[7] Med Univ Vienna, Ctr Pathobiochem & Genet, Dept Med Chem, Vienna, Austria
[8] Swiss Fed Inst Technol, Inst Mol Hlth Sci, Zurich, Switzerland
来源
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2020年 / 8卷
基金
美国国家卫生研究院; 瑞士国家科学基金会;
关键词
cholesterol synthesis; CHO cells; ER-to-Golgi transport; peroxisomes; PEX2; SCAP; SREBP-2; Zellweger syndrome; ENDOPLASMIC-RETICULUM STRESS; ELEMENT-BINDING PROTEIN; HAMSTER OVARY CELLS; LIPOPROTEIN-DERIVED CHOLESTEROL; ISOPRENOID BIOSYNTHETIC-PATHWAY; FORM TRYPANOSOMA-BRUCEI; ER STRESS; INTRACELLULAR-TRANSPORT; ZELLWEGER-SYNDROME; SQUALENE SYNTHASE;
D O I
10.3389/fcell.2020.560266
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both transcriptional and post-transcriptional feedback regulation, for which sterol regulatory element-binding proteins (SREBPs) are essential; such homeostasis is dysregulated in peroxisome-deficient Pex2 knockout mice. Here, we compared the regulation of cholesterol biosynthesis in Chinese hamster ovary (CHO-K1) cells and in three isogenic peroxisome-deficient CHO cell lines harboring Pex2 gene mutations. Peroxisome deficiency activated expression of cholesterogenic genes, however, cholesterol levels were unchanged. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein levels were increased in mutant cells, whereas HMGCR activity was significantly decreased, resulting in reduced cholesterol synthesis. U18666A, an inhibitor of lysosomal cholesterol export, induced cholesterol biosynthetic enzymes; yet, cholesterol synthesis was still reduced. Interestingly, peroxisome deficiency promoted ER-to-Golgi SREBP cleavage-activating protein (SCAP) trafficking even when cells were cholesterol-loaded. Restoration of functional peroxisomes normalized regulation of cholesterol synthesis and SCAP trafficking. These results highlight the importance of functional peroxisomes for maintaining cholesterol homeostasis and efficient cholesterol synthesis.
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页数:26
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