The HSPG/LRP pathway is also called the chylomicron remnant receptor pathway or Apo E receptor pathway. This pathway involves two cell surface receptors, HSPG (heparin sulfate proteoglycans) and LRP (LDL receptor-related protein), that clear remnant lipoproteins from hepatic cells. Initially, Apo E-containing lipoproteins bind to the cell surface of HSPG. The lipoproteins are enriched with ApoE from the HSPG and are then transferred to the LRP. The LRP then either initiates uptake or forms a complex with HSPG that is subsequently taken up by cells (Mahley et al, 1999). Not all Apo E-containing lipoproteins can bind to LRP because apolipoproteins CI and CII inhibit binding. Therefore VLDL, which contains a higher proportion of Apo CI and Apo CII, cannot be taken up by the LRP pathway. LRP is not dedicated to lipoprotein clearance. Instead, its main function involves clearing alpha2-macroglobulin from circulation.
The mineralocorticoid pathway starts with 21-hydroxylation of progesterone to form deoxycorticosterone (DOC). The enzyme in this reaction, 21-hydroxylase, is encoded by the CYP21 gene. 11 , 12 Deoxycorticosterone is then converted to corticosterone through the action of 11β-hydroxylase. There are two distinct 11β-hydroxylase isoenzymes, both of which are encoded by two genes, CYP11B1 and CYP11B2 . 13 Corticosterone is hydroxylated at carbon 18 to form 18-hydroxycorticosterone, which is transformed to aldosterone by removal of two hydrogens (oxidation) at carbon 18. These two reactions are catalyzed by 18-hydroxylase and 18-hydroxysteroid dehydrogenase, respectively, which are encoded by the same gene, CYP11B2 . Transcription of CYP11B1 is regulated primarily by ACTH, whereas angiotensin II regulates CYP11B2 transcription. 14 , 15 Similarly, the glucocorticoid pathway begins with 17α-hydroxyprogesterone, which is converted to deoxycortisol and subsequently to cortisol by 21-hydroxylase and 11β-hydroxylase, respectively, in the same manner as the conversion of progesterone to corticosterone. A deficiency of 21-hydroxylase, 11β-hydroxylase, or 3β-HSD in the adrenals may result in congenital adrenal hyperplasia and female pseudohermaphroditism, manifested as a masculinized female fetus.
Biosynthesis of steroid hormones requires a battery of oxidative enzymes located in both mitochondria and endoplasmic reticulum. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. Within mitochondria, cholesterol is converted to pregnenolone by an enzyme in the inner membrane called CYP11A1. Pregnenolone itself is not a hormone, but is the immediate precursor for the synthesis of all of the steroid hormones. The following table delineates the enzymes required to synthesize the major classes of steroid hormones.