Obesity is increasing at an alarming rate in the industrialized world. This is a serious health concern because there is a strong association between obesity and insulin resistance, type 2 diabetes, hypertension, cancer, and cardiovascular disease. Our lab is particularly interested in the link between obesity and type 2 diabetes. Type 2 diabetes currently afflicts 6-7% of the U.S. population. It is characterized by defective insulin action (insulin resistance) leading to poor control of blood glucose (sugar) levels. The disease can lead to heart disease, blindness, kidney failure, amputations, and nerve damage. Sedentary lifestyle and poor eating habits leading to obesity are contributing to the increased incidence of diabetes at all ages.

It has now become apparent that obesity-dependent insulin resistance and type 2 diabetes have characteristics of a chronic inflammatory state. This link between inflammation and insulin resistance is the focus of our lab. In one area of our work, we are testing the hypothesis that cytokines (particularly interleukin-6) contribute to inhibition of insulin receptor signaling in target tissues leading to insulin resistance. Consistent with this model, IL-6 levels are 2-3 times higher in the blood of diabetics than controls. We have demonstrated that a family of regulatory proteins, SOCS (Suppressors of Cytokine Signaling) proteins, are induced by IL-6 and other inflammatory cytokines in liver cells. SOCS proteins appear to bind to the components of the insulin receptor signaling pathway and inhibit insulin action. Thus, we propose the inflammatory environment of obesity increases expression of SOCS3 leading to insulin resistance. We are currently testing this model of obesity-dependent insulin resistance at the cellular level and with experimental animals.

The obese, type 2 diabetic has twice the risk of osteoarthritis when compared to a non-obese, non-diabetic individual. The traditional explanation for this risk is the increased bio-mechanical stress on the joint as a consequence of increased body weight. In another area of our lab's research, we have proposed an alternate explanation that attributes at least some of the progression of osteoarthritis in this population to metabolic dysregulation and chronic inflammation that is a hallmark of obesity-mediated diabetes. Recent investigations in our lab using diet-induced obese mice have provided experimental evidence to support a metabolic component to accelerated osteoarthritis progression in obesity-mediated diabetes. Ongoing investigations with genetic and dietary mouse models as well as in vitro models are being employed to define the metabolic pathways that are involved. Therapeutic modalities are also being investigated.

• Barry CT, Mills B, Hah Z, Mooney RA, Ryan CK, Rubens DJ, Parker KJ. Shear wave dispersion measures liver steatosis. Ultrasound Med Biol. 2012 Feb; 38(2):175-82.
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• Mooney RA, Sampson ER, Lerea J, Rosier RN, Zuscik MJ. High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury. Arthritis Res Ther. 2011; 13(6):R198.
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• Sampson ER, Hilton MJ, Tian Y, Chen D, Schwarz EM, Mooney RA, Bukata SV, O'Keefe RJ, Awad H, Puzas JE, Rosier RN, Zuscik MJ. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med. 2011 Sep 21; 3(101):101ra93.
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• Gough MS, Morgan MA, Mack CM, Darling DC, Frasier LM, Doolin KP, Apostolakos MJ, Stewart JC, Graves BT, Arning E, Bottiglieri T, Mooney RA, Frampton MW, Pietropaoli AP. The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis. Crit Care Med. 2011 Jun; 39(6):1351-8.
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• Clementi AH, Gaudy AM, Zimmers TA, Koniaris LG, Mooney RA. Deletion of interleukin-6 improves pyruvate tolerance without altering hepatic insulin signaling in the leptin receptor-deficient mouse. Metabolism. 2011 Nov; 60(11):1610-9.
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• Gaudy AM, Clementi AH, Campbell JS, Smrcka AV, Mooney RA. Suppressor of cytokine signaling-3 is a glucagon-inducible inhibitor of PKA activity and gluconeogenic gene expression in hepatocytes. J Biol Chem. 2010 Dec 31; 285(53):41356-65.
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• Galloway CA, Ashton J, Sparks JD, Mooney RA, Smith HC. Metabolic regulation of APOBEC-1 complementation factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes. Biochim Biophys Acta. 2010 Nov; 1802(11):976-85.
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• Clementi AH, Gaudy AM, van Rooijen N, Pierce RH, Mooney RA. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta. 2009 Nov; 1792(11):1062-72.
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• Thornburg LL, Knight KM, Peterson CJ, McCall KB, Mooney RA, Pressman EK. Maternal serum alpha-fetoprotein values in type 1 and type 2 diabetic patients. Am J Obstet Gynecol. 2008 Aug; 199(2):135.e1-5.
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• Mooney RA. Counterpoint: Interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol. 2007 Feb; 102(2):816-8; discussion 818-9.
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• Kumar SP, Mooney R, Wieser LJ, Havstad S. The LATCH scoring system and prediction of breastfeeding duration. J Hum Lact. 2006 Nov; 22(4):391-7.
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• Chagnon MJ, Elchebly M, Uetani N, Dombrowski L, Cheng A, Mooney RA, Marette A, Tremblay ML. Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma. Can J Physiol Pharmacol. 2006 Jul; 84(7):755-63.
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• Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology. 2005 Aug; 146(8):3417-27.
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• LeVea CM, Reeder JE, Mooney RA. EGF-dependent cell cycle progression is controlled by density-dependent regulation of Akt activation. Exp Cell Res. 2004 Jul 1; 297(1):272-84.
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• Klover PJ, Mooney RA. Hepatocytes: critical for glucose homeostasis. Int J Biochem Cell Biol. 2004 May; 36(5):753-8.
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• Baliff JP, Mooney RA. New developments in prenatal screening for Down syndrome. Am J Clin Pathol. 2003 Dec; 120 Suppl:S14-24.
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• Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes. 2003 Nov; 52(11):2784-9.
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• Arnold GL, Hyman SL, Mooney RA, Kirby RS. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003 Aug; 33(4):449-54.
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• Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol. 2003 Jun; 101(6):1266-74.
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• Pearce DA, McCall K, Mooney RA, Chattopadhyay S, Curran TM. Altered amino acid levels in sera of a mouse model for juvenile neuronal ceroid lipofuscinoses. Clin Chim Acta. 2003 Jun; 332(1-2):145-8.
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• Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. 2003 Apr 18; 278(16):13740-6.
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• Mooney RA, LeVea CM. The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. Curr Top Med Chem. 2003; 3(7):809-19.
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• Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002 Dec; 51(12):3391-9.
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• Symons JR, LeVea CM, Mooney RA. Expression of the leucocyte common antigen-related (LAR) tyrosine phosphatase is regulated by cell density through functional E-cadherin complexes. Biochem J. 2002 Jul 15; 365(Pt 2):513-9.
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• Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, Shang Y, Furlanetto RW. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem. 2001 Jul 13; 276(28):25889-93.
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• Levea CM, Mcgary CT, Symons JR, Mooney RA. PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer. Breast Cancer Res Treat. 2000 Nov; 64(2):221-8.
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• Opalka N, Mooney RA, Richter C, Severinov K, Landick R, Darst SA. Direct localization of a beta-subunit domain on the three-dimensional structure of Escherichia coli RNA polymerase. Proc Natl Acad Sci U S A. 2000 Jan 18; 97(2):617-22.
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• Bleyle LA, Peng Y, Ellis C, Mooney RA. Dissociation of PTPase levels from their modulation of insulin receptor signal transduction. Cell Signal. 1999 Oct; 11(10):719-25.
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• Hostetler MA, Arnold GL, Mooney R, Bennett MJ, Rinaldo P, Roe CR. Hypoketotic hypoglycemic coma in a 21-month-old child. Ann Emerg Med. 1999 Sep; 34(3):394-8.
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• Saller DN, Canick JA, Kellner LH, Rose NC, Garza J, French CA, Mooney RA. Maternal serum analyte levels in pregnancies with fetal Down syndrome resulting from translocations. Am J Obstet Gynecol. 1997 Oct; 177(4):879-81.
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• Phung TL, Mooney RA, Kulas DT, Sparks CE, Sparks JD. Suppression of the protein tyrosine phosphatase LAR reduces apolipoprotein B secretion by McA-RH7777 rat hepatoma cells. Biochem Biophys Res Commun. 1997 Aug 18; 237(2):367-71.
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• Mooney RA, Kulas DT, Bleyle LA, Novak JS. The protein tyrosine phosphatase LAR has a major impact on insulin receptor dephosphorylation. Biochem Biophys Res Commun. 1997 Jun 27; 235(3):709-12.
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• Kulas DT, Goldstein BJ, Mooney RA. The transmembrane protein-tyrosine phosphatase LAR modulates signaling by multiple receptor tyrosine kinases. J Biol Chem. 1996 Jan 12; 271(2):748-54.
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• Kulas DT, Freund GG, Mooney RA. The transmembrane protein-tyrosine phosphatase CD45 is associated with decreased insulin receptor signaling. J Biol Chem. 1996 Jan 12; 271(2):755-60.
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• Mooney RA, Arvan DA, Saller DN, French CA, Peterson CJ. Decreased maternal serum hCG levels with increasing gravidity and parity. Obstet Gynecol. 1995 Dec; 86(6):900-5.
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• Kulas DT, Zhang WR, Goldstein BJ, Furlanetto RW, Mooney RA. Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. J Biol Chem. 1995 Feb 10; 270(6):2435-8.
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• Freund GG, Wittig JG, Mooney RA. The PI3-kinase serine kinase phosphorylates its p85 subunit and IRS-1 in PI3-kinase/IRS-1 complexes. Biochem Biophys Res Commun. 1995 Jan 5; 206(1):272-8.
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• Way BA, Mooney RA. Differential effects of phosphotyrosine phosphatase expression on hormone-dependent and independent pp60c-src activity. Mol Cell Biochem. 1994 Oct 26; 139(2):167-75.
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• Mooney RA, Peterson CJ, French CA, Saller DN, Arvan DA. Effectiveness of combining maternal serum alpha-fetoprotein and hCG in a second-trimester screening program for Down syndrome. Obstet Gynecol. 1994 Aug; 84(2):298-303.
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• Freund GG, Kulas DT, Way BA, Mooney RA. Functional insulin and insulin-like growth factor-1 receptors are preferentially expressed in multiple myeloma cell lines as compared to B-lymphoblastoid cell lines. Cancer Res. 1994 Jun 15; 54(12):3179-85.
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• Way BA, Mooney RA. Activation of phosphatidylinositol-3-kinase by platelet-derived growth factor and insulin-like growth factor-1 is inhibited by a transmembrane phosphotyrosine phosphatase. J Biol Chem. 1993 Dec 15; 268(35):26409-15.
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• Freund GG, Kulas DT, Mooney RA. Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226. J Immunol. 1993 Aug 15; 151(4):1811-20.
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• Mooney RA, Freund GG, Way BA, Bordwell KL. Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1. J Biol Chem. 1992 Nov 25; 267(33):23443-6.
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• Mooney RA, Bordwell KL. Differential dephosphorylation of the insulin receptor and its 160-kDa substrate (pp160) in rat adipocytes. J Biol Chem. 1992 Jul 15; 267(20):14054-60.
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• Mooney RA, Bordwell KL. Insulin stimulates the tyrosine phosphorylation of a 61-kilodalton protein in rat adipocytes. Endocrinology. 1992 Mar; 130(3):1533-8.
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• Wilbur DC, Willis J, Mooney RA, Fallon MA, Moynes R, di Sant'Agnese PA. Estrogen and progesterone receptor detection in archival formalin-fixed, paraffin-embedded tissue from breast carcinoma: a comparison of immunohistochemistry with the dextran-coated charcoal assay. Mod Pathol. 1992 Jan; 5(1):79-84.
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• Mooney RA, Bordwell KL. Counter-regulation by insulin and isoprenaline of a prominent fat-associated phosphoprotein doublet in rat adipocytes. Biochem J. 1991 Mar 1; 274 ( Pt 2):433-8.
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• Davis NS, DiSant'Agnese PA, Ewing JF, Mooney RA. The neuroendocrine prostate: characterization and quantitation of calcitonin in the human gland. J Urol. 1989 Sep; 142(3):884-8.
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• Amatruda JM, Vallone BB, Schuster T, Mooney RA. Importance of periodic reeducation of hospital-based nurses in capillary blood glucose monitoring and an evaluation of the usefulness of reflectance meters. Diabetes Educ. 1989 Sep-Oct; 15(5):435-9.
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• Mooney RA, Green DA. Insulin receptor dephosphorylation in permeabilized adipocytes is inhibitable by manganese and independent of receptor kinase activity. Biochem Biophys Res Commun. 1989 Aug 15; 162(3):1200-6.
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• Mooney RA, Anderson DL. Phosphorylation of the insulin receptor in permeabilized adipocytes is coupled to a rapid dephosphorylation reaction. J Biol Chem. 1989 Apr 25; 264(12):6850-7.
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• Mooney RA, Bordwell KL, Luhowskyj S, Casnellie JE. The insulin-like effect of vanadate on lipolysis in rat adipocytes is not accompanied by an insulin-like effect on tyrosine phosphorylation. Endocrinology. 1989 Jan; 124(1):422-9.
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• Mayer TK, Mooney RA. Laboratory analyses for steroid hormone receptors, and their applications to clinical medicine. Clin Chim Acta. 1988 Feb 29; 172(1):1-33.
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• Mooney RA, McGorty BL, French CA, Arvan DA. An alpha-fetoprotein radioimmunoassay for use in maternal serum screening for Down's syndrome: limitations and improvements. Clin Chim Acta. 1988 Feb 15; 171(2-3):325-31.
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• Mooney RA. Use of digitonin-permeabilized adipocytes for cAMP studies. Methods Enzymol. 1988; 159:193-202.
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• Mooney RA, Swicegood CL, Marx RB. Coupling of adenylate cyclase to lipolysis in permeabilized adipocytes: direct evidence that an antilipolytic effect of insulin is independent of adenylate cyclase. Endocrinology. 1986 Nov; 119(5):2240-8.
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• Lee LA, Mooney RA, Woolf PD. Clinical utility of measuring free thyroxin and free triiodothyronine in serum of critically ill patients by ultrafiltration. Clin Chem. 1986 May; 32(5):797-800.
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• Mooney RA, McDonald JM. In situ analysis of adenylate cyclase activity in permeabilized rat adipocytes: sensitivity to GTP, isoproterenol, and N6-(phenylisopropyl)adenosine. Int J Biochem. 1986; 18(8):713-8.
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• Mooney RA, Ebersohl RD, McDonald JM. Insulin-mediated antilipolysis in permeabilized rat adipocytes. J Biol Chem. 1984 Jun 25; 259(12):7701-4.
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• Mooney RA, McDonald JM. Effect of phenylephrine on lipolysis in rat adipocytes: no evidence for an alpha-adrenergic mechanism. Int J Biochem. 1984; 16(1):55-9.
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• Mooney RA, Ebersohl RD, McDonald JM. Novel approach to the study of the regulation of hormone-sensitive lipase in rat adipocytes. Permeabilization of cells with digitonin. Eur J Biochem. 1983 Nov 15; 136(3):603-8.
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• Mooney RA, Smith CH, Zarkowsky HS. Free bilirubin measurements in a patient with Crigler-Najjar syndrome after crush injury. J Pediatr. 1983 Aug; 103(2):262-5.
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• Mooney RA, Lane MD. Control of ketogenesis and fatty-acid synthesis at the mitochondrial branch-point for acetyl-CoA in the chick liver cell: effect of adenosine 3',5'-monophosphate. Eur J Biochem. 1982 Jan; 121(2):281-7.
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• McDonald JM, Chan KM, Goewert RR, Mooney RA, Pershadsingh HA. The (Ca2+ +Mg2+)-ATPase of adipocyte plasma membrane: regulation by calmodulin and insulin. Ann N Y Acad Sci. 1982; 402:381-401.
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• Mooney RA, Lane MD. Formation and turnover of triglyceride-rich vesicles in the chick liver cell. Effects of cAMP and carnitine on triglyceride mobilization and conversion to ketones. J Biol Chem. 1981 Nov 25; 256(22):11724-33.
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• Lane MD, Mooney RA. Tricarboxylic acid cycle intermediates and the control of fatty acid synthesis and ketogenesis. Curr Top Cell Regul. 1981; 18:221-42.
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• Clinkenbeard KD, Reed WD, Mooney RA, Lane MD. Intracellular localization of the 3-hydroxy-3-methylglutaryl coenzme A cycle enzymes in liver. Separate cytoplasmic and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A generating systems for cholesterogenesis and ketogenesis. J Biol Chem. 1975 Apr 25; 250(8):3108-16.
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