B1U3: Lipids 5

Functions of cholesterol

1. key role in pathogenesis of artherosclerosis
2. important component of cell membranes (req. for membrane replication, modulates fluidity, forms rafts)
3. precursors for synthesis of steroid hormones
4. precursors for bile salt synthesis
5. biosynthetic


linear, 5-C unit of structure for the isoprenoid compounds; typical arrangement in compounds is head to tail; units are difficult to recognize in cholesterol b/c most DBs are used to form rings

Cholesterol ester

storage form of cholesterol


linear polyisoprene alcohol; very long, tends to be associated w/ membranes; participate in transfer of oligosaccharide chains during N-linked protein glycosylation


aka coenzyme Q??; consists of a quinone ring (derived from p-hrdroxyaminobenzoate) and a linear polyisoprene chain; serves as a mobile carrier of reducing equivalents btw. membrane-bound dehydrogenases and cytochrome b-c complex in e? transport chain in m

Heme A

heme structure w/ a farnesyl (C15) side chain; serves as a prosthetic group of class A cytochromes (cytochrome C oxidase complex); associated w/ e? transport chain

Isoprenylated proteins

important modification for anchoring proteins to intracellular membranes (drug target); attach via modified cysteine residues on carboxyl-terminus of protein; eg. Ras, nuclear lamins, G-protein gamma subunits, rhodopsin kinase

Simplified Cholesterol Pathway

Acetyl CoA ? acetoacetyl-CoA ? HMG-CoA (HMG-CoA reductase) ? MEVALONATE ? Isopentyl-PP ? geranyl-PP ? Farnesyl-PP (heme A, Ubiquinones, Dolichols, isoprenylated proteins) ? squalene ? cholesterol


synthesis for use in cholesterol production occurs in the cytoplasm, then it moves to ER for conversion to mevalonate; synthesis for use in ketogenesis occurs by a parallel pathway inside mitochondria, then it is converted to acetoacetate

HMG-CoA reductase

main regulatory step for cholesterol synthesis; it is irreversible and rate-limiting; converts acotoacetyl-CoA to mevalonate; it is inhibited by uptake of cholesterol in LDL; ? in dividing cells or when cellular cholesterol is low to stimulate cholesterol

Transcriptional regulation of HMG-Coa Reductase

sterol regulatory element binding proteins (SREBPs) control enzyme transcription and LDL receptor genes; mRNA levels are ? when sterol levels are high, ? when sterol level are low

Mechanism of SREBP (sterol regulatory element binding protein) regulation of HMG-CoA reductase

when cholesterol levels are low, they are released by cleavage of precursor proteins in ER membranes; they then translocate into the nucleus where they activate transcription of genes for HMG-CoA reductase & LDL recrptors, which are under control of stero

Function of Statins

Mevacor, crestor, lipitor, zocor: all are competitive inhibitors for HMG-CoA reductase which lead to stimulated production of LDL receptors (mainly in liver) to take up more circulating cholesterol (compensation for decreased cholesterol synthesis) ? circ

HMG CoA lyase vs. HMG CoA reductase

rate limiting enzymes of ketogensis and cholesterol biosynthesis respectively

Linear ? ring transformation of cholesterol

2 farnesyl-pp (condense using NADPH) ? (30-C, linear) squalene ? squalene epoxide ? protosterol cation ? lanosterol ??? (19 steps, including 7-dehydrocholesterol intermediate) ??? cholesterol


intermediate btw. lanosterol and cholesterol which serves as a precursor to vitamin D formation; lack of sunlight can cause vit. D deficiency b/c it is req. for conversion to previtamin D? ? rickets (kids) and osteomalacia (adults)

General characteristics of bile salts

polar derivatives of cholesterol (aka biliary cholesterol); produced in liver, stored in gall bladder; released into intestine (as acids) (2-3g per day); serve as effective detergents by aiding in emulsification of dietary lipids and facilitating digestio

Glycocholate and taurocholate

major bile acids; formed by condensation of cholyl-CoA w/ glycine or taurine (cysteine derivative); storage form of biliary cholesterol; stored in gall bladder; bile acids are amphipathic

Steroid hormones

hormones with the same basic sterol structure; subtle differences (in hydroxylation) underlie functional specificity


a progestagen which prepares uterine lining for implantation of ovum; essential for maintenance of pregnancy


an androgen responsible for the development of secondary sex characteristics (males)


and estrogen responsible for the development of female secondary sex characteristics and maintenance of the ovarian cycle


a glucocorticoid which promotes gluconeogenesis and glycogen utilization; enhances FA and protein degredation; inhibits inflammation


a mineralcorticoid which acts on the distal tubule of the kidney to increase Na? reabsorption and K? excretion, resulting in ? blood volume and BP

Classes of Steroid hormones (synthesized from cholesterol)

prognenolone (C21), progestagens (C21), Glucocorticoids (C21), Mineralcorticoids (C21), Androgens (C19), Estrogens (C18)

Steroid hormone pathway determined by tissue

Different pathways are active in different tissues:
glucocorticoids and mineralcorticoids: adrenal cortex
estrogens: ovary
androgens: testes
progesterone: corpus luteum

cholesterol ? pregnenolone

initiates the synthesis of steroid hormones; hydroxylation is carried out by specific mixed-function oxidases (monooxygenases) that use O? and NADPH with activation by P450 cytochromes; cleavage by desmolase removes 6-C unit

Steroid hormone pathway in the adrenal cortex

pregnenolone is oxidized to progesterone in the adrenal cortex; if 17-hydroxylase occurs first, cortisol will form; if 21- hydroxylase occurs first, corticosterone will form, eventually leading to aldosterone; there is NO interconversion btw. cortisol and

Steroid hormode pathway in ovaries and testes

pregnenolone is oxidized to progesterone in the ovaries or testes; cleavage of side chain at C17 leads to formation of androstenedione (male) which can be become estrone (female) in the presence of aromatase; reduction of keto group at C17 (of androstened

Cytochrome P450

mixed function oxidases that utilize NADPH and O? to hydroxylate steroids; more than 50 members of the family, each w/ a different substrate specificity; located primarily in the ER; enriched in liver and small intestine, but also found in other tissues;

21-hydroxylase deficiency

most common inherited disorder of steroid hormone synthesis; req. enzyme for synthesis of glucocorticoids and mineralcorticoids; leads to ? release of ACTH by anterior pituitary (b/c there is no feedback inhibition); enlarged adrenals (hyperplasia) w/ acc

Regulated proteolysis of HMG-CoA Reductase

enzyme degradation is stimulated by oxidized derivatives of cholesterol taken up w. LDL; membrane spanning part of enzyme has a sterol-sensing domain ? may have a role in activating degradation


used to prevent resorption of bile acids as a cholesterol reducing agent; less bile recycling ? hepatic cholesterol redirected to synthesis of bile acids resulting in a net ? of blood cholesterol