Metabolomics/Metabolites/Lipids/Steroids

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1. Cholesterol

Steroids

Steroid is a chemical name for any substance that has a characteristic chemical structure consisting of multiple rings of connected atoms. Vitamin D, cholesterol, estrogen, and cortisone are some examples of steroids. Various steroids have important roles in the body’s reproductive system and the structure and function of membranes. It has been discovered that steroids can be active in the brain, where they affect the nervous system. Some steroids are used as anesthetics. Douglas Covey of Washington University in St. Louis, Missouri, has uncovered new roles for several of these neurosteroids, which alter electrical activity in the brain. Covey’s research shows that neurosteroids can either activate or tone down receptors that communicate the message of a neurotransmitter called gammaaminobutyrate, or GABA. The main job of this neurotransmitter is to dampen electrical activity throughout the brain. Covey and other scientists have found that steroids that activate the receptors for GABA decrease brain activity even more, making these steroids good candidates for anesthetic medicines. Covey is also investigating the potential of neuroprotective steroids in preventing the nerve-wasting effects of certain neurodegenerative disorders.

Progesterone and Estrogen

Progesterone

Estriol form of Estrogen

The neurotrophic and neuroprotective effects of progesterone and estrogen have been confirmed to support reproductive and cognitive health. These steroids have recently been proven to also regulate metabolic processes, in order to meet specific energetic requirements for cognitive maintenance. Fully comprehending this metabolic control necessitated interpreting signals from a variety of environmental sources that were integrated by receptor-mediated responses that converged upon mitochondrial function. Research involved treating ovariectomized rats with progesterone (P4), 17 -estradiol (E2) or E2+P4, and functionally assessing isolated whole brain mitochondria, in order to determine the effects of P4 and E2 on metabolic control. The brain mitochondria of the hormone treated rats exhibited enhanced functional efficiency and increased metabolic rates. In addition, the same mitochondria displayed an increase in respiratory function that was coupled to an increase in expression, and electron transport chain complex IV activity (cytochrome c oxidase). The enhanced mitochondrial efficiency was a result of this increased respiratory activity that was accompanied by a decreased rate of reactive oxygen leak, and reduced lipid peroxidation.

Exclusive administration of E2 to the mitochondria resulted in a significant increase in complex IV (COX) activity. Specifically, brain mitochondria treated with E2 were prevented from ethanol withdrawal-induced declination of COX activity. In vitro studies exhibited a direct concentration dependent interaction between estrogens and ATPase activity; an increase in estrogen concentration raised ATPase activity, and a decrease in estrogen concentration lowered ATPase activity. By consequence, ATP levels and oxidative stresses were determined to be directly dependent upon the interaction of steroids with oligomycin-sensitivity conferring proteins (OSCP), which act as the binding sites for E2, in the mitochondria. Treatment of the mitochondria with E2 also resulted in lower levels of lipid peroxidation at a constant rate of H2O2 production. This indicated an increase in cellular antioxidant defenses. Furthermore, tightly coordinated regulation of mtDNA and nDNA encoded in mitochondrial genes made it impossible to identify whether or not hormones act at a nuclear site to regulate COXIV in order to increase COXI, II, and III expression, or vice versa, as a result of E2 and P4 acting at both sites. Despite this, all attempts to analyze combined effects of P4 and E2 resulted in a substantial decrease in mitochondrial response. In summation, mitochondrial alterations in the central nervous system that were induced by ovarian hormonal replacements induced efficient and balanced bioenergetics that reduced oxidative stress, and the occurrence of endogenous oxidative damage.

References:

Design Medicines (2006): n. pag. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Institute of General Medical Sciences. Web.<http://www.nigms.nih.gov>.

http://endo.endojournals.org/cgi/rapidpdf/en.2007-1227v1

Biochemistry Metabolites/Lipids/Steroids

KEGG Pathway: A. Synthesis and degradation of Ketone Bodies http://www.genome.ad.jp/kegg/pathway/map/map00072.html B. Biosynthesis of Steroids: http://www.genome.ad.jp/kegg/pathway/map/map00100.html 1. C12- Steroid Hormone Metabolism: http://www.genome.ad.jp/kegg/pathway/map/map00140.html a. Androgen and Estrogen Metabolism http://www.genome.ad.jp/kegg/pathway/map/map00150.html 2. Bile Acid Biosynthesis: http://www.genome.ad.jp/kegg/pathway/map/map00120.html

MetaCyc Pathway: A. MetaCyc Pathway: sterol biosynthesis http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-2541 B. MetaCyc Pathway: cholesterol biosynthesis I http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY66-341 C. MetaCyc Pathway: cholesterol biosynthesis II http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY66-4 D. MataCyc Pathway: brassinosteroid biosynthesis I http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-699 E. MataCyc Pathway: brassinosteroid biosynthesis II http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-2582 F. MetaCyc Pathway: ginsenoside biosynthesis http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-5672 G. MetaCyc Pathway: ergosterol biosynthesis http://BioCyc.org/META/NEW-IMAGE?type=PATHWAY&object=ERGOSTEROL-SYN-PWY

General Web Resources: A. Steroids General Information Basic http://en.wikipedia.org/wiki/Steroid B. Anabolic steroid http://en.wikipedia.org/wiki/Anabolic_steroid

Image of Common Steroid Molecules: A. Lanosterol See more information about Lanosterol on wikipedia -> http://en.wikipedia.org/wiki/Lanosterol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=246983

B. Cycloartenol See more information about Cycloartenol on wikipedia-> http://en.wikipedia.org/wiki/Cycloartenol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=92110

C. Sterol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1107

D. Estrogen (Estriol, Estradiol, and Estrone) See information on wikipedia -> http://en.wikipedia.org/wiki/Estrogen Estriol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5756

Estradiol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5757

Estrone

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5870

E. Progesterone

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5994

F. Testosterone

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6013

G. Cholesterol

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5997

Web Resources General Description: A. Steroid Hormone Metabolism http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism.html

Main focus of the resource: A well-defined explanation of steroids and their uses in metabolic systems; includes information on steroid hormones structures, nomenclature and classification, as well as the biosynthesis pathways. In addition, this source demonstrates key ways the steroids are used as metabolites.

New terms: 1. Androgenic- any substance, such as testosterone or androsterone that promotes male characteristics. 2. Aromatase- an enzyme or complex of enzymes that promotes the conversion of an androgen (as testosterone) into estrogens (as estradiol). 3. Adrenal - At, near, or on the kidneys; relating to the adrenal glands or their secretion. 4. Pseudohermaphroditism - an individual having internal reproductive organs of one sex and external sexual characteristics resembling those of the other sex or being ambiguous in nature. 5. Lipophilic - promoting the dissolvability or absorbability of lipids

Connection to Course: Steroids are essential in metabolic processes to elicit biological responses. Steroid metabolism is important in the production of hormones, and for the regulation of their cellular and physiological actions. An important function of the steroid hormones is to coordinate responses for specific biological purposes, such as reproduction and sex differences, which is the main focus of this article. Although we did not focus greatly on steroids and how they impact reproduction and sex differences it is still an important part of their impact on our body. In chapter 10, pg. 359 our course textbook briefly touches on this subject and how steroids are vital in communicating message to other bodily tissues.

Web Resources General Description: B. The Nomenclature of Steroids http://www.chem.qmul.ac.uk/iupac/steroid/3S01.html

Main focus of the resource: This is an excellent recourse that explains the nomenclature of steroids; includes information on stereochemistry, functional groups, configuration, number and ring structure. In addition this source also has history of the nomenclature of steroids.

New terms: 1. Addendum- an appendix to a book 2. Gonane- parent tetracyclic hydrocarbon without methyl groups at C-10 and C-13 and without a side chain at C-17 3. Triterpenoids- Terpenoids having a C30 skeleton. 4. Heterocyclic- Of a cyclic compound that contains one or more atoms other than carbon in at least one of its rings. 5. Heteroatoms- any atom in a heterocyclic ring (or other structure normally built of carbon atoms) that is not a carbon atom

Connection to Course: In order to understand how chemical reactions occur in living organisms to maintain life we must begin to understand the chemicals themselves, therefore knowing the structures of steroids is essential to understanding their metabolic processes. In our studies it is vital to understand their structures so we can understand how they interact with other molecules in metabolic pathways, modulate cell function, or regulate metabolism.

Web Resources General Description: C. Steroid Hormones http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Steroids/Steroids.HTML

Main focus of the resource: Great general overview of steroids and that includes classes of steroids, structures, functions and roles, regulation and control. This is an excellent resource that explains a little bit of everything about steroids allowing the reader to gain a general understanding of steroids.

New terms: 1. Sterol- subgroups of steroids with a hydroxyl group in the 3-position of the A-ring. 2. Phytosterols- Sterols of plants 3. Terpenoids- having a C30 skeleton. 4. Glucocorticoids- are a class of steroid hormones characterized by an ability to bind with the glucocorticoid receptor and trigger similar effects. 5. Peripheral- near the surface or outside of; external.

Connection to Course: Steroids regulate many aspect of metabolism by interacting with our immune function, our response to receptors to increase synthesis; they adjust fluidity of the cell membrane, and are altogether vital to how our body functions. This website gives an insight to the breakdown of how these processes work and how steroids play this critical role. In studying steroids we have taken a close look at cholesterol and how it interact with the cell membrane of tissues, this is because it plays such an important role in biochemical possesses.

Additional General Websites: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192076

Article General Description: A. Regulation of Hepatic 7-Hydroxylase Expression and Response to Dietary Cholesterol in the Rat and Hamster http://www.jbc.org/cgi/content/full/270/10/5381

Main focus of the resource: In this study researchers look at ovarian hormones and their neurotrophic effects on reproductive function and cognitive health. They did this by studying these steroids ability to regulate metabolic functions in rats. From this study they observed brain mitochondria from hormone- treated rats displayed enhanced functional efficiency and increased metabolic rates.

New terms: 1. Myocardium- the muscular substance of the heart.. 2. Ovariectomized- to surgically remove an ovary from 3. Neurotrophic- of, or pertaining to the effect of nerves on the nutritive processes. 4. Cytochrome- any of several carrier molecules in the mitochondria of plant and animal cells, consisting of a protein and an iron-containing porphyrin ring and participating in the stepwise transfer of electrons in oxidation reactions 5. Neuroprotective- serving to protect neurons from injury or degeneration.

Connection to Course: This article demonstrates how vital the mitochondria, which regulates the energy balance of the cell, is to our body and how steroids can impact it. Steroids that impact the mitochondria can in turn impact many specialized physiological functions of the cell. In the study of steroids we have seen in this course how steroid hormones have the ability do so and an example of this would be how progesterone, and ovarian hormone, can provide nerve function and healing by regulating myelin.

Article General Description: B. Progesterone and Estrogen Regulation Oxidative Metabolism in the Brain Mitochondria http://www.jstage.jst.go.jp/article/hypres/30/11/30_1029/_article

Main focus of the resource: In this study researchers are examining the fact that human populations show a strong correlation between dietary cholesterol intake and coronary heart disease due to its effects on plasma low density lipoprotein (LDL) cholesterol. Due to the response to a given intake of cholesterol varying among different species and even in individuals of the same species, this study looks at the mechanisms responsible for differing sensitivity. This was performed by comparing rats, which is able to adapt to fluctuations, with hamsters, who where more sensitive to changes in LDL levels. From this study they observed that the response to dietary cholesterol in these two species spans the range of individual responses observed in humans.

New terms: 1. Aorta- the main trunk of the arterial system, conveying blood from the left ventricle of the heart to all of the body except the lungs. 2. Aliquots- Of, relating to, or denoting an exact divisor or factor of a quantity, especially of an integer. 3. Hepatic- of or pertaining to the liver. 4. Diurnal- of or pertaining to a day or each day; daily.. 5. Isotopic- any of two or more forms of a chemical element, having the same number of protons in the nucleus, or the same atomic number, but having different numbers of neutrons in the nucleus, or different atomic weights.

Connection to Course: This article directly demonstrates what we have been discussing in class; see chapter 21 pg. 825 for detailed diagram of impact of LDL particle. These processes along with dietary uptake of cholesterol and breakdown of how Acetyl-CoA is assembled into cholesterol have all been present to us in lecture.

Article General Description: C. Integration of progesterone receptor action with rapid signaling events in breast cancer models

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8X-4PP2CR6-

5&_user=47004&_coverDate=02%2F29%2F2008&_alid=696051811&_rdoc=5&_fmt=full&_ori g=search&_cdi=5098&_sort=d&_docanchor=&view=c&_ct=1514&_acct=C000005018&_versio n=1&_urlVersion=0&_userid=47004&md5=836f85277049cb84df9f8cff596cb06f

Main focus of the resource: In looking at breast cancer progression this study examines the underlying molecular mechanisms of uncontrolled cellular growth in breast cancer. They hope to understand how the estrogen and progesterone receptor action contribute to the development and progression of breast cancer.

New terms: 1. Aspartic- pertaining to, or derived, asparagine; as, aspartic acid. 2. Mitogen– any substance or agent that stimulates mitotic cell division 3. Autocrine- Of or relating to self-stimulation through cellular production of a factor and a specific receptor for it. 4. Myometrium- the smooth muscle forming the wall of the uterus 5. Ligand- a molecule, as an antibody, hormone, or drug, that binds to a receptor.

Connection to Course: Steroid hormones and their receptors exert direct effects in the nucleus as transcription factors and function at the membrane and cytosol as mediators in signaling pathways. This process of mediating signaling pathways has been demonstrated throughout this course and more information on this topic can be found in chapter 21 Lipid Biosynthesis of the course textbook. This chapter demonstrates the regulation and balance of dietary uptake.