Clinical Case Study Q41
A 55-year-old woman presented with classical clinical features of Cushing’s syndrome including hypertension, diabetes mellitus, central obesity and easy bruising. She denied previous depression or heavy alcohol intake and was not receiving any steroid containing medication.
Question 1: List the causes of Cushing’s syndrome and discuss what initial investigations you would perform?
Question 2: In the light of these results, what additional tests would you perform?
Question 3: What is the likely cause of this patient’s recurrent Cushing’s and what further investigations should be performed?
Introduction To Cholesterol Metabolism
Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as being a precursor for the synthesis of the steroid hormones, the bile acids, and vitamin D. Both dietary cholesterol, and that synthesized de novo, are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells. Due to its important role in membrane function, all cells express the enzymes of cholesterol biosynthesis.
The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. Of particular clinical importance is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.
Structure of cholesterol
Electrocyclizations Without Subsequent 6 Electrocyclization
Vitamin D3 is synthesized in the skin of vertebrates through the participation of a cholesterol derivative in a pericyclic cascade involving a 6 conrotatory electrocyclic ring opening, followed by an antarafacial sigmatropic hydride shift. Vitamin D3 is then hydroxylated in the liver to yield 25-hydroxyvitamin D3 and hydroxylated further in the kidneys to yield 1,25-dihydroxyvitamin D3, a potent ligand of the vitamin D receptor. The propensity of these natural substances to partake in pericyclic reactions was used in the preparation of conformationally locked analogs of 1,25-dihydroxyvitamin D3 .88 Cyclooctatriene 371 was prepared via a thermal conrotatory 8 electrocyclization of 370, generated in situ by the partial reduction of trieneyne 369 under Lindlar conditions. The cyclization was torquoselective, where bond formation occurs via an equatorial attack on the trans-fused hexahydroindene moiety. The cyclooctatriene product does not undergo a subsequent 6 electrocyclization, presumably due to the strained nature of the resulting spiro-compound.
Scheme 64. Synthesis of vitamin D3 analogs.
Scheme 65. Electrocyclic transformation of squarate esters.
Table 16. Electrocyclic transformation of squarate esters
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Martin Kohlmeier, in, 2015
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Steroidogenic Acute Regulatory Protein
The first step in classical steroid hormone biosynthesis involves the conversion of cholesterol into pregnenolone by the cholesterol side chain cleavage enzyme P450scc . Although the side chain cleavage reaction is known to be the rate-limiting enzyme for adrenal and gonadal steroid hormones, it is not the catalytic process of the cholesterol side chain cleavage enzyme that is rate limiting.
A specific cholesterol transport protein, known as the steroidogenic acute regulatory protein , has been implicated as being the essential mediator of cholesterol delivery to the mitochondria and the consequent activation of P450scc . StAR is biosynthesized as an ~300-amino acid protein with a binding pocket for a single cholesterol molecule. StAR has a mitochondrial targeting sequence of 25 amino acid residues, which is cleaved from the NH2-terminus after it is transported into the mitochondria. More specifically, the rate limiting step in classical steroid hormone biosynthesis is the presence and properties of the StAR at the outer mitocondrial membrane where it facilitates the movement of cholesterol across the OMM to the IMM site of the P450scc. It is known that the adrenal tropic ACTH hormone can rapidly stimulate the gene transcription of StAR in the adrenal cortex which then is the exclusive mediator of the transport of cholesterol from the OMM to the IMM.
Anthony W. Norman, Gerald Litwack, in, 1997
The Synthesis Of Cholesterol
Finally, the biosynthesis of cholesterol is here with the simplest discussion ever:
- 5-pyrophosphomevalonate is formed from Mevalonate. This occurs in the presence of a kinase.
- 5-pyrophosphomevalonate is decarboxylated to isopentyl pyrophosphate . This occurs in the presence of decarboxylase and ATP.
- IPP is converted to 3-3-dimethylallyl pyrophosphate . This takes place in the presence of isomerase.
- IPP and DPP condense to form geranyl pyrophosphate .
- The second molecule of IPP combines with GPP forming Farnesyl pyrophosphate .
- Two molecules of FPP combine to form 6 isoprenoid unit squalene. This reaction occurs in the presence of squalene synthase.
- Squalene is converted to lanosterol, catalyzed by squalene monooxygenase. This enzyme uses molecular oxygen and NADPH. The hydroxylation of squalene triggers the cyclization of cholesterol.
- In a multistep process, lanosterol is converted to cholesterol and as a result, the following things occur:
- shortening of carbon chains from 30 to 27 carbons
- removal of two methyl groups at carbon number 4
- migration of double bonds from C-8 to C-5
- reduction of a double bond between C-24 and C-25
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The Biosynthesis Of Hmg
The synthesis of HMG-CoA takes place in the following steps:
- 2 acetyl CoA molecules combine to form acetoacetyl- CoA, in the presence of enzyme thiolase.
- The 3rd molecule of acetyl CoA is added to form 3-Hydroxy-3-Methylglutaryl CoA . This takes place in the presence of enzyme HMG-CoA synthase. It is a cytosolic enzyme.
Role Of Gh In Cholesterol And Lipid Metabolism
There exists a negative relationship between obesity and GH. Enormous evidence supports that GH alters lipid metabolism. Clinical studies have shown a significant association between lower serum GH levels and non-alcoholic fatty liver disease . Hypopituitary patients with GH deficiency are more prone to NAFLD than control subjects . GH supplementation has been shown to improve the NAFLD and the metabolic dysfunction . In rodent studies, high-fat diet feeding and obesity suppress pulsatile GH secretion . In turn, chronic GH treatment ameliorates hepatic lipid peroxidation and improves lipid metabolism in high-fat diet-fed rats .
GHR is present in the liver and critical for the hepatic lipid metabolism. Laron dwarfism is a disorder characterized by an insensitivity to GH due to a genetic mutation of GHR. These male patients manifest NAFLD in adults . Liver-specific deletion of GHR in mice leads to increased circulating free fatty acids and fatty liver as a result of increased synthesis and decreased efflux of triglyceride . Binding of GH to GHR activates JAK2-STAT5 signaling pathway and modulates a number of target genes. Among these, altered expression of CD36, PPAR and PGC1/, along with fatty acid synthase, lipoprotein lipase and very-low-density lipoprotein receptor contributes to the hepatic lipid metabolism process . All these findings suggest that hepatic GH signaling is essential for the regulation of intrahepatic lipid and cholesterol metabolism.
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Liver Microsomal Subfractions From Animals Treated With Xenobiotics
In an attempt to see whether the distribution of OST subunits, translocon components, and chaperones in adrenal microsomes was simply related to the larger amount of SER in adrenocortical cells, we prepared liver microsomal subfractions from animals treated with PB and 3MC. These compounds are known to induce the cytochrome P450s that metabolize them, CYPs 2B and 1A, respectively, as well as other enzymes involved in metabolism of foreign compounds. These enzymes are located predominantly in the SER, and their induction leads to an increase in the amount of SER in hepatocytes . In the treated animals, the relative amount of protein in the smooth microsomal fraction reached levels comparable with adrenal smooth microsomes . Each xenobiotic agent induced the appropriate CYP: PB treatment resulted in increased levels of CYP2B and 3MC treatment resulted in increased levels of CYP1A, particularly in the smooth microsomes .
Potential Future Therapies For Hyperlipidemia
apoC-III Inhibitors
Several other potential targets have been identified that may prove useful for pharmacological intervention of hyperlipidemias and hypercholesterolemias. The apolipoprotein apoC-III inhibits the activity of endothelial lipoprotein lipase as well as hepatic lipase. Individuals harboring loss-of-function mutations in the APOC3 gene have significantly reduced levels of circulating triglycerides suggesting that targeting this protein may be an effective treatment of hypertriglyceridemias. An ASO approach to knocking down the circulating level of apoC-III is currently in phase 2 clinical trials.
Angiopoietin-Like Protein Inhibitors
CETP Inhibitors
Numerous epidemiological and clinical studies over the past 15 years have demonstrated a direct correlation between the circulating levels of HDL cholesterol and a reduction in the potential for atherosclerosis and coronary heart disease . Individuals with levels of HDL above 50mg/dL are several time less likely to experience CHD than individuals with levels below 40mg/dL. In addition, clinical studies demonstrated that when apolipoprotein A-I , or reconstituted HDL are infused into patients there was an increase in the level of circulating HDL and reduced incidence of CHD. Thus, there is precedence for therapies aimed at raising HDL levels in the treatment and prevention of atherosclerosis and CHD. Unfortunately current therapies only modestly elevate HDL levels.
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Squalene Cyclization Yields The First Sterol Intermediate
The reactions shown here are catalyzed by squalene epoxidase and lanosterol synthase. The rearrangement indicated by the dashed arrow is not a real reactionââ¬âwe just rotate a couple of single bonds to show how the pieces fall into place for the subsequent cyclization.
The oxygen is introduced by squalene epoxidase, a cytochrome P450 enzyme. Such enzymes use NADPH to reduce one of the two atoms of molecular oxygen, while retaining the other one in a highly reactive state, which they then use toward their specific purposes . Squalene synthase inserts its active oxygen into a C=C double bond of the substrate to form an epoxide. The subsequent cleavage of the epoxide by lanosterol synthase starts a cascade of reactions that goes from one end of the molecule to the other, closing all four rings of the sterol skeleton in the process. Note that a methyl group also changes its place on the sterol ring the reaction mechanism is quite intricate.
11.2.6
Microsomal Subfraction Protein And Ribosome Content
As expected, based on the morphology of the cells , smooth microsomes comprised a considerably greater percentage of the total microsomal fraction prepared from adrenals of control animals than from the liver, whereas rough microsomes were more abundant in liver . However, when animals were treated with xenobiotics, which induce the SER in hepatocytes, the liver smooth microsomal fraction increased, reaching levels comparable with those in adrenal smooth microsomes.
The smooth microsomal subfraction represents over 75% of total microsomal proteins obtained from adrenal tissue, but 2535% of control liver total microsomes. Treatment of animals with agents known to increase CYPs and other enzymes involved in xenobiotic metabolism increased the relative amount of smooth microsomes from liver tissue 2-fold. The percent of total microsomal protein in each microsomal fraction was calculated for fractions obtained from control guinea pig adrenal and for liver tissue from control guinea pigs and rats. These were compared with corresponding data derived from liver tissue of guinea pigs treated with 3MC, known to induce CYP1A, and rats treated with PB, known to induce CYP2B. The values shown represent the mean ± sem of three microsomal preparations for guinea pig liver and four for guinea pig adrenal and rat liver.
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Deficiency Of Adrenocortical Secretions
Worldwide, the most common cause of Addison’s may still be tuberculosis but in Western countries autoimmune disease is a more common cause of adrenal failure . A relatively recent development has been the effect of the human immunodeficiency virus . This has increased the incidence of hypoadrenalism due to infectious agents including viruses such as cytomegalovirus, fungi such as histoplasmosis, coccidiomycosis or blastomycosis, bacteria such as tuberculosis or the drugs that are used to treat these agents. AIDS itself may be associated with generalized resistance to glucocorticoid effects of cortisol. illustrates some of the clinical features of Addison’s disease.
Skin pigmentation. Melanins are made from tyrosine. The initial reaction involves the enzyme tyrosinase subsequent enzymic reactions form complex polymers. In the absence of cysteine, eumelanin is formed, in the presence of this amino acid pheomelanin
Two Membrane Proteins Control The Uptake Of Sterols From The Intestine
The uptake of cholesterol by intestinal epithelial cells begins with endocytosis. This process is controlled by NPC1L1, a membrane protein which is deficient in a lipid storage disorder known as Niemann-Pick disease. NPC1L1 is a sterol sensor and promotes cholesterol uptake through endocytosis.
From the endocytotic vesicles, cholesterol is transferred to the endoplasmic reticulum by the microsomal triglyceride transfer protein . Acylation by acyl-CoA cholesterol acyltransferase yields a cholesterol ester, which is loaded into a nascent chylomicron together with triacylglycerol. After the chylomicrons have been released from the intestinal cells and reached the circulation via the lymphatics , most of their triacylglycerol is depleted by capillary lipoprotein lipase. The cholesterol stays behind in the chylomicron remnants, which are taken up and utilized in the liver .
In contrast to what its name suggests, MTTP transports not only triacylglycerol but also sterols. Mutational inactivation of this protein results in abetalipoproteinemia.70 Such patients have reduced levels of chylomicrons and are affected by malabsorption of lipids and of lipid-soluble vitamins.
11.4.4
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Cotranslational Translocation Signal Peptide Cleavage And N
To confirm that the activities of translocon, SPC and OST components could be coordinated in adrenal smooth microsomes, we assayed the ability of adrenal microsomal subfractions to translocate peptides synthesized on ribosomes bound to these membranes as well as to cleave signal peptides and N-glycosylate incoming, newly synthesized polypeptides. The adrenal smooth microsomal subfractions were at least as capable of these functions as adrenal rough microsomal subfractions . However, the levels of both activities were considerably lower than in dog pancreatic rough microsomes. Comparison of the levels of N-glycosylation of the opsin fragment with the levels of oligosaccharyltransferase activity measured using the OTP acceptor , suggest that the amount of processing observed reflects the rate of targeting and translocation of the newly synthesized heterologous polypeptides rather than the full capacity of these enzyme complexes.
Proteolytic Cleavage In The Golgi Releases Srebp
Once SREBP reaches the Golgi, it is ambushed and cleaved by two specific proteases . Cleavage releases the DNA-binding domain of the protein from the membrane. This fragment then moves across the cytosol and enters the nucleus, where it binds to SRE sequence elements that increase the expression of HMG-CoA reductase and also of various other enzymes from the cholesterol synthesis pathway .
Another protein that is upregulated by SREBP and SRE is the LDL receptor, a membrane protein that mediates endocytosis of low density lipoprotein . In cells that do not synthesize cholesterol themselves, SREBP upregulates transcription of the LDL receptor,
Like SREBP and SCAP, HMG-CoA reductase is anchored in the ER membrane. This does not seem necessary for the chemistry it performs. Instead, this location facilitates the negative feedback regulation imposed on it by cholesterol. Indeed, the enzyme contains a sterol-sensing domain that is homologous to the one found in SCAP .
11.4
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What Hormones Related To Cholesterol
Cholesterol occurs in every cell of the body, and since in all human bodies it is stored in the adrenal glands, it has a vital role in synthetizing those steroid hormones, which are produced by the adrenals. Steroid hormones produced in human body include corticoids and androgens. Cholesterol is synthesized in the liver and hence, drugs which inhibit livers production also have a very damaging effect upon the proper production of hormones.
Non Steroid Hormones Are Synthesized From
Steroid hormones are produced from a lipid called cholesterol. Nonsteroid hormones include proteins, small peptides, and modified amino acids. Lesson Overview.
Developmental targets of hormones are the meristems (stem cells.
pathways in specific developmental contexts. Ethylene is synthesized from methionine. The ethylene receptors are localized.
It wasnt until 1931 that testosterone was synthesized, making it available for scientific study. But by then, the idea that testosterone was a male sex hormone tied to vitality and strength had taken.
justified in concentrating on just this portion of “nonsteroid hormones.” The.
Synthesis of a-MSH using blocking groups derived from.
12.06.2019.
Steroid hormones are derived from cholesterol and are synthesized.
Non-alcoholic fatty liver disease is a metabolic disorder.
Nonsteroid hormones are synthesized from: A)amino acids.
E)Most of the endocrine glands produce steroid hormones. B)Some endocrine glands,
Steroid-producing cells lack secretory granules and do not store significant amounts of preformed hormone. They are dependent on continued biosynthesis to.
TSH is synthesized in the pituitary gland and is regulated by both TRH and the thyroid hormone negative feedback system .
The initial electronic database search retrieved 6214 potential studies with 3 additional studies retrieved from citations . After removal of 2679 duplicates and reviewing the titles and.
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When Cholesterol Is Low Srebp Is Sorted To The Golgi Apparatus
At low cholesterol concentrations, SCAP binds to another membrane protein that recruits it into nascent vesicles, and it takes SREBP along for the ride. When these vesicles bud off from the ER membrane, they travel to the Golgi apparatus and fuse with its membrane. The Golgi is a cellular organelle that performs many types of posttranslational protein modification, such as glycosylation, lipid modification, and proteolytic processing.
11.3.3
Treatment Of Addison’s Disease
Once suspected, it is imperative that Addison’s disease is confirmed biochemically and that it is treated immediately. underwent biochemical confirmation using the short tetracosactrin test . This showed a low basal serum cortisol concentration of 50 nmol/l and no response to this synthetic ACTH . On completion of the test, she was given an intravenous injection of 100 mg hydrocortisone and an intravenous infusion of 1 liter of normal saline as she maintained her refusal to be admitted to hospital. She was given 9-fludrocortisone 100 g daily as mineralocorticoid replacement and 100 mg cortisol thrice daily tailing to a maintenance of 20 mg daily in divided doses. felt much improved within hours of receiving hydrocortisone.
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