3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human hair roots

Brannan, Patricia G.; Goldstein, Joseph L.; Brown, Michael S.

doi:10.1016/s0022-2275(20)36745-6

Cited by 30 publications

(5 citation statements)

References 15 publications

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“…It is hard to comment on any changes that may occur in enzyme concentration and activation state in the time between the removal of the skin from the patient, and isolation of the glands, but the results presented here are consistent with those measuring rates of incorporation of radiolabeled acetate into lipids by isolated glands, which in turn are consistent with rates of lipid production by the glands in vivo (Leyden et al, 1981;Kealey et al, 1986;Barth et al, 1989;Guy et al, 1996). The time of sampling is approximately midday, which would correspond to the rat diurnal high; however, when human hairs were plucked at various times and then assayed, no diurnal variation was observed (Brannan et al, 1974).…”

Section: Discussionsupporting

confidence: 84%

“…This supports an earlier observation by Goldstein, Brown, and colleagues. Using hair follicles plucked from individuals who differed greatly in their plasma cholesterol levels, they showed that HMG-CoA reductase activity in these follicles is not regulated by LDL in vivo (Brannan et al, 1974). In this study, LDL induced a significant stimulation of hair follicle HMG-CoA reductase activity.…”

Section: Discussionmentioning

confidence: 49%

“…Few studies, however, have looked at the individual steps important in the control of these synthetic pathways. Goldstein, Brown, and colleagues assayed plucked human scalp hairs and found HMG-CoA reductase highly active (Brannan et al, 1974). Proksch et al (1990) detailed the activity of HMG-CoA reductase in murine skin, and on examining its activity in intact, stripped, and protected skin, they showed that the transepidermal water barrier regulates the concentration and activation state of the epidermal enzyme.…”

Section: Discussionmentioning

confidence: 99%

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The Activity of HMG-CoA Reductase and Acetyl-CoA Carboxylase in Human Apocrine Sweat Glands, Sebaceous Glands, and Hair Follicles Is Regulated by Phosphorylation and by Exogenous Cholesterol

Smythe

Greenall

Kealey

1998

Journal of Investigative Dermatology

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Human apocrine and sebaceous glands function to secrete lipids, predominantly triglycerides, fatty acids, cholesterol and its esters, and, in the sebaceous gland, squalene. The enzymes that catalyze the important regulatory steps in cholesterol and fatty acid biosyntheses, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acetyl-CoA carboxylase, respectively, were therefore studied in isolated human skin appendages, and their relevant kinetic parameters determined. The enzyme activities that were observed can account for previously described rates of incorporation of radiolabeled substrates into the appropriate lipids by glands in vitro. Reduced enzyme activities following homogenization in the presence of fluoride indicated that both of these enzymes in skin appendages are inactivated by phosphorylation. The activity of the enzyme known to catalyze this phosphorylation, the AMP-activated protein kinase, was also measured. Compactin was shown to inhibit HMG-CoA reductase in homogenates of these appendages. Conversely, incubation of whole sebaceous glands with compactin resulted in the stimulation of enzyme activity, which suggests that these appendages can respond to diminishing cholesterol levels. The effect of exogenous low density lipoprotein and 25-hydroxycholesterol on HMG-CoA reductase activity from skin appendages was investigated. HMG-CoA reductase activity in both apocrine and sebaceous glands was reduced following incubation with either low density lipoprotein or 25-hydroxycholesterol. Low density lipoprotein receptor and lipoprotein lipase mRNA expression was also detected in skin appendages. These results indicate that apocrine and sebaceous glands have the capacity to sequester dietary cholesterol and fatty acids that may have important implications for the understanding of both acne and axillary odor.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

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The Activity of HMG-CoA Reductase and Acetyl-CoA Carboxylase in Human Apocrine Sweat Glands, Sebaceous Glands, and Hair Follicles Is Regulated by Phosphorylation and by Exogenous Cholesterol

Smythe

Greenall

Kealey

1998

Journal of Investigative Dermatology

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“…There may also be a difference in the nature or number of the postulated receptors on the lymphocyte compared with the fibroblast. One possible example that such differences exist has been reported by Brannan, Goldstein, and Brown (Brannan et al, 1975). They observed that the activity of HMG CoA reductase measured in hair roots in normal individuals does not change, despite manipulations of plasma cholesterol levels by medications that strikingly alter the activity of the enzyme in human liver.…”

Section: Discussionmentioning

confidence: 98%

Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and the esterification of cholesterol in human long term lymphoid cell lines

Kayden¹,

Hatam²,

Beratis³

1976

Biochemistry

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The regulation of the rate-controlling enzyme in cholesterol biosynthesis and of the incorporation of [14C]oleate into cholesterol esters were studied in established lymphoid cell lines from normal subjects and compared with that of eight patients with genetic abnormalities of lipid metabolism. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, increases in lymphoid cell lines derived from normal subjects after the culture medium is changed to a lipid deficient medium and reaches peak activity after 48 hr. The addition of whole serum and of low density lipoproteins to cell lines derived from normal subjects suppressed 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by 50%, but failed (almost completely) to suppress the activity in the lymphoid cell lines derived from two patients with homozygous familial hypercholesterolemia. When 7-ketocholesterol was added, the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase was markedly suppressed in both normal and abnormal lymphoid cell lines. Lymphoid cell lines derived from patients presumably heterozygous for familial hypercholesterolemia were difficult to distinguish from normal cells in these studies. The incorporation of [14C]oleate into the fatty acid fraction of cholesteryl esters was stimulated by the addition of the low density lipoproteins to the culture media of the lymphoid cell lines derived from the normal human subjects. The lymphoid cell lines derived from the patients with homozygous familial hypercholesterolemia showed no increase in [14C]oleate incorporation into cholesteryl esters even when a fourfold amount of low density lipoprotein was added to the media; a modest increase in [14C]oleate incorporation was observed in lymphoid cell lines from patients with heterozygous familial hypercholesterolemia. The results of these studies in lymphocyte cell lines are compared with the findings in cultured human fibroblasts obtained from normal subjects and from patients with homozygous familial hypercholesterolemia. Studies of the regulation of cholesterol biosynthesis in the apparently permanent lymphoid cell line maintained in suspension culture offer certain advantages over cultured skin fibroblasts, and, in addition, provide a second tissue for the study of genetic abnormalities from the same patient.

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“…Recent studies have revealed that hair follicles have the capacity for intrafollicular de novo biosynthesis of cholesterol, with a key enzyme, 24-dehydrocholesterol reductase (DHCR24), being highly expressed in these follicles. 24-dehydrocholesterol reductase is crucial in converting desmosterol to cholesterol, contributing to the cholesterol levels necessary for proper hair follicle function (Brannan et al, 1975; Mizra et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Cholesterol Biosynthesis and Hair Follicle Stem Cell Impairment in the Onset of Alopecia

Nikhila,

Surya,

Najeeb

et al. 2023

Preprint

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BackgroundHair follicle cycle and the functioning of stem cells in alopecia are influenced by the suppression of cholesterol synthesis and the accumulation of sterol intermediates.ObjectiveThis investigation aims to elucidate the regulatory function of disrupted cholesterol homeostasis in the functioning of hair follicle stem cells (HFSCs) and the cycling of hair follicles. Additionally, it seeks to provide an understanding of the fate of stem cells in primary cicatricial alopecia (PCA).MethodsTo evaluate the influence of cholesterol on the functionality of hair follicles, a study was conducted to analyse gene expression and pathways associated with hair follicle stem cell markers in scalp samples affected by PCA (LPP, FFA, CCCA, DC, DF, TF). To assess the influence of disrupted cholesterol homeostasis on HFSCs, we conducted experiments involving the administration of 7-dehydrocholesterol (7DHC) and BM15766 (Pharmacological inhibitor of cholesterol biosynthesis), to Human Hair Follicle Outer Root Sheath Cells (HORSCs), as well as C57BL/6 mice, and hair follicle organoid cultures. The study utilised reverse transcription polymerase chain reaction (RT-PCR) to assess gene expression, while immunofluorescence was employed to analyse protein expression. The tracking of stem cell fate was accomplished through the utilisation of a BrdU pulse-chase experiment, while the verification of apoptotic consequences was established by utilising the TUNEL assay. A statistical analysis was conducted to assess the statistical significance of the data.ResultsThere was a notable decrease in the expression of HFSC marker genes among patients afflicted with PCA.In vitrodata further confirmed the cholesterol inhibition and sterol intermediate accumulation in stem cells, leading to stem cell characteristics’ disruption. The experimental group of mice exposed to 7DHC and BM15766 also exhibited a notable inability to initiate hair regrowth. Consequently, this deficiency in hair regrowth resulted in the activation of apoptosis, specifically in the stem cells. Additionally, our confirmatory analysis, which was performed utilising organoid culture, consistently yielded comparable results. The results as mentioned above emphasise the significant importance of cholesterol production in preserving the integrity and functionality of HFSCs, hence providing novel insights into the progression of alopecia.ConclusionIndividuals with aberrant cholesterol production, particularly those afflicted with PCA, experience a persistent impairment in hair regrowth due to the irreversible destruction of their hair follicles. The observed phenomenon is hypothesised to be attributed to the loss of hair follicle stem cells. Our study presents additional findings that elucidate the previously unknown involvement of sterol intermediates in regulating hair follicle cycling and stem cell function in PCA. The regulation of cholesterol production and the buildup of sterol intermediates have an impact on the hair follicle cycle and the role of stem cells in alopecia.

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3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human hair roots

Cited by 30 publications

References 15 publications

The Activity of HMG-CoA Reductase and Acetyl-CoA Carboxylase in Human Apocrine Sweat Glands, Sebaceous Glands, and Hair Follicles Is Regulated by Phosphorylation and by Exogenous Cholesterol

The Activity of HMG-CoA Reductase and Acetyl-CoA Carboxylase in Human Apocrine Sweat Glands, Sebaceous Glands, and Hair Follicles Is Regulated by Phosphorylation and by Exogenous Cholesterol

Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and the esterification of cholesterol in human long term lymphoid cell lines

Disrupted Cholesterol Biosynthesis and Hair Follicle Stem Cell Impairment in the Onset of Alopecia

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