Cholesterol and the steroid hormones part 2: biosynthesis

Sources of cholesterol
1. Diet
  1. Receptor mediated uptake uptake of LDL/HDL cholesterol from the circulation
    1. LDL deposit cholesterol
    2. HDL take up cholesterol from the tissues
2. De novo synthesis (in steroid-secreting cells)
  1. Radioactive work established all of synthesised cholesterol's carbon atoms came from acetate
  2. Approximately 50% of the body's cholesterol is from de novo biosynthesis
    1. 10% from the liver
    2. 15% from the intestines
  3. Occurs in the cytoplasm and ER of steroid-secreting cells
    1. Uses acetate as building blocks - forming acetyl-CoA
      1. Series of steps from acetyl-CoA to build the steroid nucleus
        A key enzymes in this process is HMG-CoA reductase (= rate limiting step)
        An integral protein of the ER membrane
        Rate limiting step of cholesterol synthesis - heavily regulated
        Also a target for pharmaceutical agents (e.g. statins)
        Statins contain a region that is analogous to mevaldehyde/mevalonate
        Clinical trials show that statins greatly reduce blood cholesterol levels and and reduce the risk of cardiovascular disease
        Regulation of HGM-CoA reductase
        HMG-CoA
        HMG-CoA reductase
        (Mevaldehyde) -> mevalonate
        ->->->-> farnesyl-PP
        x2 Squalene
        Cholesterol
        Oxidised cholesterol
        +
        Farnesyl-P
        +
        Pi
        (long term regulation) - DEGRADATION of HMG-CoA reductase
        (short term regulation) - INACTIVATION of HMG-CoA reductase
        +
        AMPK
        +
        High AMP (low ATP)
        +
        Insulin and thyroid hormones
        -
        Glucagon and glucocorticoids
        Hormonal regulation of HMG-CoA reductase
        STATINS
        e.g. lovastatin, zocor etc.
        Acetyl-CoA + acetoacetyl-CoA
        HMG-CoA synthase
        -> HMG-CoA
        HMG-CoA reductase
        (active site intermediate = mevaldehyde) -> mevolanate
        Farnesyl-pyrophosphate (PP)
        x2 Squalene
        Cholesterol
        2NADPH - > 2NADP(+) + HS-CoA
3. Cholesterol-ester stores (in steroid-secreting cells)
  1. Steroid-secreting cells
    1. Feature lipid droplets
    2. Lots of SER
    3. Mitochondria with tubular christae
      1. Mitochondria appear circular (characteristic)
      2. Sites of steroid synthesis
  2. Cholesterol is stored in lipid dorplets within the cell as a cholesterol ester (Cholesterol + acetyl-CoA)
    1. This is catalysed by ACAT (acetyl-CoA cholesterol acetyl transferase)
      1. Acetyl-CoA + Cholesterol -> Cholesterol-ester (CE)
      2. When cholesterol is need for steroid synthesis the reverse reaction is catalysed by; CE-hydrolase
        CE -> Cholesterol + acetate
        Cholesterol -> steroid biosynthesis pathway
      3. ACAT is found in the ER
Steroidogenesis
1. Rate limiting step
  1. The rate of delivery to the inner mitochondrial membrane
    1. Early studies showed that protein synthesis inhibtion also inhibited steroidogenesis - suggesting a rapidly synthesised protein was inportant in this
      1. Two candidates;
        StAR (Steroidogenesis acute regulatory protein)
        37kDa precursor in response to cAMP
        Short half-life
        Active at the level of the outer mitochondrial membrane
        Mitochondrial importation of StAR results in the generation of the 30kDa mature StAR protein and terinates its activity
        PBR (Peripheral benzodiazapine receptor
        High affinity cholesterol binding protein
        Located in the outer mitochondrial membrane
        Abundant where outer and inner membranes contact
        Mutation/down-regulation: inhibition of steroidogenesis
        Deletion: lethal phenotype
        PBR drug ligands affect cholesterol transport into mitochondria
        Both are needed to get cholesterol across the mitochondrial membrane
        StAR insertion into the outer mitochondrial membrane allows PBR to form a channel(?)
  2. (Surprisingly) not the rate of cholesterol uptake, synthesis by the cell or the activity of the enzyme P450scc...
    1. P450 = enzyme that catalyses the conversion of cholesterol into pregnenolone (the first step of steroidogenesis)
2. Enzymes of steroid biosynthesis
  1. Mostly members of the CYP gene family
    1. Encode cytochrome P450 enzymes - catalyse hydroxylations
      1. Found in all steroid hormone producing and metabolising cells
  2. Other enzymes are hydroxysteroid dehydrogenases (HSDs)
  3. Steroidogenesis map
    1. CHOLESTEROL
      1. P450scc (side chain cleavage)
        PREGNENOLONE
        3-beta-HSD
        PROGESTERONE
        P450c21 hydroxylase
        DEOXYCORTICOSTERONE
        P450 11 beta Hydroxylase
        CORTICOSTERONE
        Aldosterone synthase
        ALDOSTERONE
        P450 17alpha hydroxylase
        P450 17alpha hydroxylase
        17-alpha -OH- PRENENOLONE
        3-beta-HSD
        17-alpha -OH- PROGESTERONE
        P450c21 hydroxylase
        DEOXYCORTISOL
        P450 11 beta Hydroxylase
        CORTISOL
        P450 17alpha hydroxylase
        ANDROSTENEDIONE
        Aromatase
        ESTRONE
        17beta-HSD
        ESTRADIOL
        P450 17, 20 Lyase
        DHEA
        3-beta-HSD
        17beta-HSD
        TESTOSTERONE
        5alpha reductase
        DIHYDROTESTOSTERONE
        Aromatase
    2. Red = enzyme; green = progestogens; yellow= mineralocorticoid; blue = androgens and orange = oestrogens
  4. In the mitochondria and SER (steroids move betwen these compartments by an unknown mechanism)

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Cholesterol and the steroid hormones part 2: biosynthesis

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