AbstractsBiology & Animal Science

Studies on the Transcriptional and Enzymatic Control of Steroid Metabolism: Regulation by Lysosomal Acid Lipase, 24-Dehydrocholesterol Reductase, and Amyloid Precursor Protein

by Wei Wang

Institution: University of Helsinki
Department: Institute of Biomedicine, Anatomy; Minerva Foundation Institute for Medical Research
Year: 2013
Keywords: medicine
Record ID: 1144138
Full text PDF: http://hdl.handle.net/10138/41877


Cholesterol is an essential structural component of mammalian cells. It is taken up by cells from low density lipoproteins (LDL) where it is stored as cholesteryl esters. Cholesterol can also be synthesized by cells from precursor sterols, such as desmosterol. In cells, cholesterol can be further metabolized to other bioactive molecules, including steroid hormones. In this thesis, we explored selected aspects in the regulation of steroid metabolism. The three studies included in the thesis focused on lysosomal acid lipase (LAL), 24-dehydrocholesterol reductase (DHCR24), and amyloid precursor protein (APP). LAL hydrolyzes cholesteryl esters and generates free cholesterol, while DHCR24 converts desmosterol to cholesterol. APP is the precursor of the pathogenic Aβ peptide in Alzheimer s disease. The physiological function of APP is not known but it has recently been implicated in the regulation of cholesterol metabolism. We characterized the uptake and LAL-mediated degradation of LDL-derived steroid esters in mammalian cells. Although the cellular breakdown of LDL-carried cholesteryl esters is well characterized, the pathway for LDL-derived steroid hormone esters is less well understood. Our results showed that dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) in LDL particles could be taken up by LDL receptors, after which DHEA-FAE was hydrolyzed partially by LAL and converted into two major metabolites, 5α-androstanedione and androstenedione. We also addressed the potential functions of desmosterol, an intermediate precursor of cholesterol, during brain development. Desmosterol transiently accumulates in the developing brain of mammalian species; however, it is not known how this happens, nor what the desmosterol accumulation might serve for. We provided evidence that the DHCR24 enzyme is repressed by progesterone, and that desmosterol accumulation parallels gestational progesterone accumulation. Furthermore, we proposed desmosterol promotes sterol secretion from glial cells and maintains an ample supply of active sterols in the developing brain. Finally, we investigated how APP regulates cholesterol metabolism in mammalian cells. APP has mostly been studied in neurons but the protein is ubiquitously expressed. In this study, we found that APP and its proteolytic fragments regulate cholesterol biosynthesis and LDL-uptake via the transcription factor SREBP2. We also showed that in glial cells two APP ectodomains, APPsα and APPsβ, acted opposingly in cholesterol synthesis regulation, depending on the APP α- vs. β-cleavage. Kolesteroli on nisäkässolujen välttämätön rakenneosa. Solut ottavat sitä sisäänsä veren LDL-partikkeleista, joissa kolesteroli on varastoituna kolesteroliestereinä. Solut myös tekevät itse kolesterolia steroliesiesteista, kuten desmosterolista. Soluissa kolesterolia voidaan edelleen muokata muiksi bioaktiivisiksi molekyyleiksi, esim. steroidihormoneiksi. Tässä väitöskirjassa selvitimme steroidiaineenvaihdunnan säätelyä. Tutkimuksen kolme osatyötä käsittelivät hapanta lipaasia (LAL),…