Cholesterol Biosynthesis and Regulation: Role of Peroxisomes

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

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Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

Scientific Reports ◽

10.1038/s41598-021-02267-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rachna Manek ◽

Yao V. Zhang ◽

Patricia Berthelette ◽

Mahmud Hossain ◽

Cathleen S. Cornell ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Animal Behavior ◽

Phenylalanine Hydroxylase ◽

Cholesterol Biosynthesis ◽

Blood Phenylalanine ◽

Liver Functions ◽

Unknown Lipid ◽

Pah Gene

AbstractPhenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

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Secondary regulatory sites in rat liver cholesterol biosynthesis: Role of 5-pyrophosphomevalonate decarboxylase

Lipids ◽

10.1007/bf02540970 ◽

1980 ◽

Vol 15 (3) ◽

pp. 196-199 ◽

Cited By ~ 27

Author(s):

Ana María Jabalquinto ◽

Emilio Cardemil

Keyword(s):

Rat Liver ◽

Cholesterol Biosynthesis ◽

Liver Cholesterol ◽

Regulatory Sites

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HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways

Cancers ◽

10.3390/cancers11091363 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1363 ◽

Cited By ~ 2

Author(s):

Hyeji Kang ◽

Taerim Oh ◽

Young Yil Bahk ◽

Geon-Hee Kim ◽

Sang-Yeon Kan ◽

...

Keyword(s):

Cholesterol Biosynthesis ◽

Metabolic Stress ◽

Mapk Signaling ◽

Heat Shock Factor 1 ◽

Antiproliferative Effects ◽

Proteotoxic Stress ◽

Cholesterol Biosynthesis Pathway ◽

Increased Activity ◽

Essential Transcription Factor

Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.

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Role of Multidrug Resistance P-glycoproteins in Cholesterol Biosynthesis

Journal of Biological Chemistry ◽

10.1074/jbc.271.5.2634 ◽

1996 ◽

Vol 271 (5) ◽

pp. 2634-2640 ◽

Cited By ~ 72

Author(s):

James E. Metherall ◽

Huijuan Li ◽

Kathleen Waugh

Keyword(s):

Multidrug Resistance ◽

Cholesterol Biosynthesis

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The role of a 5α-hydroxylated intermediate in the formation of the 5, 6-double bond in cholesterol biosynthesis

Biochemical Journal ◽

10.1042/bj1450345 ◽

1975 ◽

Vol 145 (2) ◽

pp. 345-352

Author(s):

K Alexander ◽

M Akhtar

Keyword(s):

Double Bond ◽

Enzyme System ◽

Cholesterol Biosynthesis ◽

Biological Conversion ◽

Partial Denaturation

If the biological conversion of cholest-7-en-3beta-ol (I) into cholesterol (IV) occurred thorugh the intermediacy of cholest-7-ene-3beta,5alpha-diol (II) then the factor(s) adversely affecting the convwesion of the 5alpha-hydroxy sterol (II) into cholesterol must at least equally adversely affect the formation of cholesterol from cholest-7-en-3beta-ol. By using partial denaturation techniquws and dual-labelled precursors it was shown that the enzyme system responsible for the conversion of the 5alpha-hydroxy sterol (II) into cholesterol denatured faster than that for the corresponding conversion from cholest-7-en-3beta-ol (I).

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Role of 8(14) monoene sterols in cholesterol biosynthesis

Life Sciences ◽

10.1016/0024-3205(70)90231-6 ◽

1970 ◽

Vol 9 (21) ◽

pp. 1201-1205 ◽

Cited By ~ 3

Author(s):

A. Fiecchi ◽

A. Scala ◽

F. Cattabeni ◽

E. Grossi Paoletti

Keyword(s):

Cholesterol Biosynthesis

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The Intermediary Role of Δ5,7-Cholestadien-3 β-ol in Cholesterol Biosynthesis

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)91325-6 ◽

1964 ◽

Vol 239 (5) ◽

pp. 1381-1387 ◽

Cited By ~ 20

Author(s):

Mary E. Dempsey ◽

Jennie D. Seaton ◽

George J. Schroepfer ◽

Rachel W. Trockman

Keyword(s):

Cholesterol Biosynthesis ◽

Intermediary Role

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APOE2, E3 and E4 differentially modulate cellular homeostasis, cholesterol metabolism and inflammatory response in isogenic iPSC-derived astrocytes

10.1101/2021.07.17.452644 ◽

2021 ◽

Author(s):

Sherida de Leeuw ◽

Aron WT Kirschner ◽

Karina Lindner ◽

Ruslan Rust ◽

Witold E Wolski ◽

...

Keyword(s):

Proteomic Analysis ◽

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

Glutamate Uptake ◽

Cholesterol Biosynthesis ◽

Average Risk ◽

Proteomic Data ◽

Human Astrocytes ◽

Β Amyloid

Apolipoprotein E (APOE) is the principal lipid carrier in the CNS and mainly expressed by astrocytes. The three different APOE alleles (E2, E3, and E4) impose differential risk to Alzheimers disease (AD); E2 is protective, E3 is defined as average risk, while E4 is the major genetic risk factor for sporadic AD. Despite recent advances, the fundamental role of different APOE alleles in brain homeostasis is still poorly understood. To uncover the functional role of APOE in human astrocytes, we differentiated human APOE-isogenic iPSCs (E4, E3, E2 and APOE-knockout (KO)) to functional astrocytes (hereafter: iAstrocytes), with a resting, non-proliferating phenotype. Functional assays indicated that polymorphisms in APOE (APOE4>E3>E2=KO) reduced iAstrocyte metabolic and clearance functions including glutamate uptake and receptor-mediated uptake of β-amyloid aggregates. We performed unlabelled mass spectrometry-based proteomic analysis of iAstrocytes at baseline and after activation with interleukin-1β showing a reduction of cholesterol and lipid metabolic and biosynthetic pathways, and an increase of immunoregulatory pathways at baseline (E4>E3>E2). Cholesterol efflux and biosynthesis were reduced in E4 iAstrocytes, and subcellular localization of cholesterol in lysosomes was increased. In APOE-KO iAstrocytes, APOE-independent mechanisms showed to be proficient in mediating cholesterol biosynthesis and efflux. Proteomic analysis of IL-1β-treated iAstrocytes showed an increase of cholesterol/lipid metabolism and biosynthesis as well as inflammatory pathways. Furthermore, cholesterol efflux, which was reduced in APOE4 iAstrocytes at baseline, was alleviated in activated E4 iAstrocytes. Inflammatory cytokine release was exacerbated upon IL-1β treatment in E4 iAstrocytes (E4>E3>E2>KO), in line with the proteomic data. Taken together, we show that APOE plays a major role in several physiological and metabolic processes in human astrocytes with APOE4 pushing iAstrocytes to a disease-relevant phenotype, causing dysregulated cholesterol/lipid homeostasis, increased inflammatory signalling and reduced β-amyloid uptake while APOE2 iAstrocytes show opposing effects. Our study provides a new reference for AD-relevant proteomic and metabolic changes, mediated by the three main APOE isoforms in human astrocytes.

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