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Estrogen+PUFA Esters May Drive Obesity; Most Doctors Have Not Even Heard Of Them

Discussion in 'Scientific Studies' started by haidut, Feb 21, 2018.

  1. haidut

    haidut Member

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    An unassailable dogma in endocrinology is that menopause is characterized by low estrogen levels. The fact that plasma levels are only indicative of ovarian activity is conveniently overlooked, as is the fact that fat tissue grows after menopause and fat is the primary source of estrone (estrone easily converts into estradiol as needed). This study below highlights yet another aspect of estrogen overload that is unknown to most endocrinologists - i.e. estrogen forms esters with fatty acids (primarily PUFA, as the study shows) and these get delivered to target tissues, and are almost never tested for in common steroid panel bloodwork. This specific study found those estrogen+PUFA esters to be correlated with obesity and insulin resistance in both men and women. I suspect that they also play a role in many other diseases for which mainstream medicine mistakenly claims there is actual "deficiency" of estrogen (since the blood tests do not capture those esters). I don't know if there is a lab test that a doctor can order to test for these, but the actual point here is that estrogen is almost never in a state of deficiency and it is certainly not deficient in obesity, diabetes and menopause (as doctors claim). I also suspect that the formation of these esters with PUFA but not SFA is not a coincidence either, as PUFA synergizes with estrogen and facilitates its entry into the cell by changing the "membrane" rigidity (on which @Travis can shed more light). An SFA+estrogen ester (if it exists at all) will likely not be very effective at both entering the cell and binding with the estrogen receptors. Finally, given the similar chain length of some SFA (palmitic, stearic, etc) and estrogen, I suspect that some of those SFA can actually bind the estrogen receptor and act as competitive antagonists there. My suspicion is not just a random guess, but is based on a few older studies showing remarkable pro-androgenic effects of saturated fats. I will post these studies later this week.

    Plasma oestrone-fatty acid ester levels are correlated with body fat mass in humans. - PubMed - NCBI
    "...The metabolites of steroidal hormones, including sulphate, glucuronide, and fatty acid ester derivatives, have received little attention, although these steroid derivatives are essential components in the global assessment of steroid metabolism. The presence of steroidal fatty acid esters (-FA) was characterized many years ago, and almost every family of steroid is known to occur in esterified form (Hochberg et al., 1991). Analysis of the distribution of the -FA derivatives, as pregnenolone and DHEA (PREG-FA and DHEA-FA) in lipoproteins has revealed the presence of lipoidal steroids in all major lipoprotein classes, but predominantly in low density lipoproteins (LDL) and very low density lipoproteins (VLDL), which are transferred from high density lipoproteins (HDL) by a cholesteryl ester transfer protein-independent mechanism (Roy & Be´langer, 1989, 1990; Provencher et al., 1992). Circulating PREG-FA and DHEA-FA have been consistently found in an epidemiological study of more than 2000 men (Be´langer et al., 1994). It has been shown that obese men are characterized by lower plasma levels of total testosterone and adrenal steroids compared to lean individuals (Pasquali et al., 1991; Tchernof et al., 1995), and higher oestradiol (Schneider et al., 1979) and oestrone levels (Brind et al., 1990). In a recent study, androstane-3a, 17b-diol glucuronide was found to constitute a steroid correlate of visceral obesity in men (Tchernof et al., 1997). Oestradiol-17-fatty acid esters have been found in human blood and in fat (Janocko & Hochberg, 1983; Larner et al., 1992). These levels are considerably higher in ovarian follicular fluid (Larner et al., 1993). In the latter, the unsaturated esters, arachidonate, oleate, and linoleate, comprised 76% of the total oestradiol-17-fatty acid esters (Larner et al., 1993). They are believed to serve as a sequestered source of oestrogen which elicit prolonged oestrogenic responses, providing oestradiol by action of hydrolytic esterases, not requiring de novo steroidogenesis. Testosterone fatty acid esters have also been characterized in the rat (Kishimoto et al., 1973; Borg et al., 1995)."

    "...In this study plasma E1-FA concentration was found to correlate with body fat in men and women. This correlation could be due to increased oestrone formation and esterification with fatty acids in adipose tissue. The latter hypothesis is based, in addition to our findings, on the following facts:
    -- Adipose tissue is one of the main sites for oestrogen synthesis (Vague et al., 1984a, b; Deslypere et al., 1985; Simpson et al., 1981, 1989, 1996; Lueprasitsakul et al., 1990; Labrie et al
    1991), as it contains a sizable aromatase activity (Cleland et al., 1985; Yamada & Harada, 1990);
    -- In men, the circulating levels of oestrone correlated with adipose tissue mass in one study (Zumoff et al., 1981);
    -- Oestrone is the most abundant oestrogen in the blood, both in women and men (Remy-Martin et al., 1993);
    -- The available evidence suggests that weight loss is associated with changes in steroid hormone concentrations (Stanick et al., 1981; Jakubowicz et al., 1996).

    We have also found an association, independently of body fat, between E1-FA levels and insulin sensitivity in men, but not in women. Leptin levels are also associated with insulin sensitivity, independently of body fat, in men but not in women, so the known relationships between body fat content, insulin sensitivity and leptin (Segal et al., 1996; Kennedy et al., 1997) were mirrored by plasma E1-FA levels. The latter might be related to the interaction of E1-FA with leptin (Sanchis et al., 1997) and its well known sexual dimorphism (Kennedy et al., 1997). We cannot exclude a potential physiological role of E1- FA through peripheral conversion to estradiol (Longcope & Tait, 1971; Deslypere et al., 1985). In this way, it is interesting to note that the obese gene has a consensus sequence of the oestrogen-responsive element in its promoter region (Kumar & Chambon, 1988; Savouret et al., 1994), and high affinity oestrogen binding macromolecules are present in the cytosolic fraction of various adipose tissues (Wade & Gray, 1978). Furthermore, oestrogen receptors are found in human mature adipocytes from both women and men (Pedersen et al., 1996). In a recent study, oestradiol was a powerful stimulator of leptin release in adipose tissue obtained from women, but not from men, suggesting a sex-dependent regulation of leptin secretion in human adipocytes (Casabiell et al., 1998). The latter finding would explain the higher leptin concentration in women’s blood as well as the leptin changes throughout the menstrual cycle (Hardie et al., 1997)."
     
  2. lollipop

    lollipop Guest

    Following.
     
  3. Obi-wan

    Obi-wan Member

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    We are slowly but surely getting @Travis into hormone discussions
     
  4. Travis

    Travis Member

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    The entire class of fibrate drugs—all of which bind to PPARα—appear as if they've been modeled after steroid–fatty acid esters, giving the impression that PPARα is responsible for sensing cholesterol esterification within the cell.

    'Within cells, modified LDL-derived cholesteryl esters are hydrolyzed in lysosomes to free cholesterol. This free cholesterol is probably initially transported to the plasma membrane where it integrates in the cell membrane. [The presence of cholesterol into the membrane lowers fluidity and promotes cell membrane rigidity.] Excess membrane cholesterol is transported back to the endoplasmic reticulum where it is re-esterified by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) with fatty acids and stored as lipid droplets. Thus, the cholesterol esterification rate also controlled by fatty acid availability depends partially on their catabolism by enzymes such as carnitine palmitoyltransferase 1 CPT-1, a key enzyme regulating mitochondrial fatty acid entry. [Palmitic acid (16∶0) is shuttled by carnitine, and is probably to longest saturated fatty acid that needs to be. The shorter-chained fatty acids don't need carnitine transport, perhaps explaining part of the reason for their higher rates of β-oxidation.]' ―Chinettii

    'Similar effects were observed with other specific PPARα ligands, such as ciprofibrate, bezafibrate, fenofibric acid, and GW647 at concentrations specifically activating human PPARα. Under these conditions, no net increase in total cholesterol accumulation was observed with any of the drugs tested. These data suggest a role for PPARα in the control of macrophage cholesterol esterification.' ―Chinetti

    ppar2.png click to embiggen

    'In human macrophages and foam cells, treatment with fibrates, synthetic PPARα activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARα activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARα activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARα activation blocked CE formation induced by TNF-α, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-α. In conclusion, our results identify a role for PPARα in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.' ―Chinetti

    'These actions of PPARα are not due to a decreased expression of the ACAT1 gene, the enzyme responsible for cholesteryl ester formation in macrophages, because ACAT1 mRNA levels do not change. By contrast, PPARα agonists increase the expression of CPT-1, an enzyme located in the mitochondrial outer membrane catalyzes the entry of long chain fatty acids into the mitochondria, thus determining the flux of fatty acids into mitochondria for β-oxidation. Increased expression of CPT-1 mRNA may thus result in a reduced availability of long chain ratty acids as substrate for ACAT1, thus leading to decreased cholesterol esterification.' ―Chinetti

    ppar.png click to embiggen

    'Treatment with different PPARα activators significantly induced the expression of CPT-1 mRNA levels in primary human monocyte-derived macrophages. This induction occurred in a dose-dependent manner, as shown for Wy14643. The effects on CPT-1 induction by Wy14643 correlated with the observed reduction of cholesteryl ester levels. These observations provide one potential mechanism by which PPARα controls cholesteryl ester accumulation.' ―Chinetti

    'In conclusion, our results demonstrate a novel role for PPARα in the control of the balance between free cholesterol and cholesteryl esters, an effect which, associated with the induction of ABCA1, may contribute to enhanced liberation and efflux of free cholesterol and stimulation of the initial step of the reverse cholesterol transport pathway.' ―Chinetti

    In a straightforward manner, Chinetti had examined how the cholesterol ester to free cholesterol ratio had been modified by PPARα ligands—testing my suspicion directly with radio-labeled oleic acid. The total cholesterol concentration did not change, although PPARα ligands caused a shift towards more free cholesterol and fatty acids; this is what you'd expect if PPARα's natural role is to sense the endogenous cholesterol ester concentration, homeostatically-maintaining a steady-state level by acting accordingly. The main enzyme you'd expect to be changed by this process—the acyltransferase—hadn't been, but it had been found that a carnityl transferase was. At first this had seemed contradictory, but after looking at the molecular structure of carnitine it's readily apparent what is going on:

    [​IMG]

    The mitochondria attracts all positively-charged molecular species due to it's high negative charge, the highest anywhere in the cell at −180·mV. In fact, molecules with multiple positive charges (i.e. TMRE) are used to stain mitochondria and to measure its potential by how much accumulates on its surface. Thus, all fatty acids attached to carnitine could logically be expected to be attracted to the mitochondria as a function of diffusion and fundamental ionic attraction. Differential intracellular localization isn't determined solely by positive charges, but also by the highly-negatively-charged phosphate groups which can 'tag' anything destined for the membrane. It has been shown receptors can be localized by phosphorylation by site-directed mutagenesis, with appearances on the cell membrane being a direct function of the number of phosphorylated serine's present. Uncharged molecules, and especially those lipid-soluble and of high density, appear to localize within the nucleus. Cell mechanisms behind intracellular localization which depend on the isoelectric point of the diffusing molecule are the both intuitive and realistic, and also gives a teleological meaning to phosphate signalling and carnityl transfers.

    'Our results demonstrate that, without influencing total cholesterol accumulation in macrophages, PPARα activation reduces the cholesterol free∶ester ratio in macrophages and macrophage-derived foam cells by inhibiting cellular cholesteryl ester formation activity.' ―Chinetti

    The PPARα receptor is also a transcription factor, physically interacting with DNA to transcribe the segments it wants. So when sensing a fibrate drug, or very likely an endogenous steroid ester, it induces mRNA for the enzyme carnitine palmitoyltransferase—an enzyme naturally found in the vicinity of the cell membrane that covalently attaches carnitine to palmitic acid, giving it the positive charge necessary to be attracted by the mitochondria. This makes fibrates a candidate for performance-enhancing drugs, and it's no coincidence that they're used for this very reason.

    'In 2007 research was published showing that high doses of GW501516 given to mice dramatically improved their physical performance; the work was widely discussed in popular media, and led to a black market for the drug candidate and to its abuse by athletes as a doping agent. ' ―Wikipedia

    So the PPARα do not reduce steroid esters concentrations directly—by modifying the levels of the enzyme which makes them—but by tagging long chained fatty acids with carnitine for mitochondrial β-oxidation; whatever is burned by the mitochondrial cannot later be attached to a steroid, and the acyltransferase probably can't even use carnityl–fatty acids. The nuclear receptor and transcription factor PPARα senses steroid esters and drugs which resemble it, and you might expect any uncharged molecule having both cyclic rings and an ester group as being a potential PPARα ligand.

    Chinetti, G. "Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARα, PPARγ, and LXR." Biochemical and biophysical research communications (2004)
    Chinetti, G. "Peroxisome proliferator-activated receptor α reduces cholesterol esterification in macrophages." Circulation research (2003)
     
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