Effect of cutaneous permeability barrier disruption on HMG-CoA reductase, LDL receptor, and apolipoprotein E mRNA levels in the epidermis of hairless mice.

S M Jackson,L C Wood,S Lauer,J M Taylor,A D Cooper,P M Elias,K R Feingold

doi:10.1016/s0022-2275(20)40544-9

Abstract

Disruption of the permeability barrier results in an increase in cholesterol synthesis in the epidermis. Inhibition of cholesterol synthesis impairs the repair and maintenance of barrier function. The increase in epidermal cholesterol synthesis after barrier disruption is due to an increase in the activity of epidermal HMG-CoA (3-hydroxy-3-methylglutaryl CoA) reductase. To determine the mechanism for this increase in enzyme activity, in the present study we have shown by Western blot analysis that there is a 1.5-fold increase in the mass of HMG-CoA reductase after acute disruption of the barrier with acetone. In a chronic model of barrier disruption, essential fatty acid deficiency, there is a 3-fold increase in the mass of HMG-CoA reductase. Northern blot analysis demonstrated that after acute barrier disruption with acetone or tape-stripping, epidermal HMG-CoA reductase mRNA levels are increased. In essential fatty acid deficiency, epidermal HMG-CoA reductase mRNA levels are increased 3-fold. Thus, both acute and chronic barrier disruption result in increases in epidermal HMG-CoA reductase mRNA levels which could account for the increase in HMG-CoA reductase mass and activity. Additionally, both acute and chronic barrier disruption increase the number of low density lipoprotein (LDL) receptors and LDL receptor mRNA levels in the epidermis. Moreover, epidermal apolipoprotein E mRNA levels are increased by both acute and chronic perturbations in the barrier. Increases in these proteins in response to barrier disruption may allow for increased lipid synthesis and transport between cells and facilitate barrier repair.

Highlights

Disruption of the permeability barrier results in an increase in cholesterol synthesis in the epidermis
Our studies have demonstrated that the increase in 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase activity in the epidermis after barrier disruption is due to both dephosphorylation of the enzyme and an apparent increase in the quantity of enzyme determined by measuring activity in microsomes isolated in NaCl buffer [10]
A statistically significant, 1.5-fold increase in the quantity of HMG-CoA reductase was found in the acetone-treated versus control flanks (Fig. l), an increase in HMG-CoA reductase content that is similar to the increase in total enzyme activity at the same timpeoint [10]

Summary

Introduction

Disruption of the permeability barrier results in an increase in cholesterol synthesis in the epidermis. In a chronic model of barrier disruption, essential fatty acid deficiency, there is a 3-fold increase in the mass of HMG-CoA reductase. The stimulation of epidermal cholesterol synthesis after barrier disruption, in both the acute and chronic models, is due to an increase in the activity of HMG-CoA reductase (lo), the rate-limiting enzyme in cholesterol synthesis. Our studies have demonstrated that the increase in HMG-CoA reductase activity in the epidermis after barrier disruption is due to both dephosphorylation (activation) of the enzyme and an apparent increase in the quantity of enzyme determined by measuring activity in microsomes isolated in NaCl buffer [10]. We determined whether the regulation of other proteins that are important in cholesterol homeostasis, such as the LDL receptor and apoE, were altered by barrier disruption

Methods

Results

Conclusion