Michihisa Umetani, Ph.D.
Department of Biology and Biochemistry
Office: SERC, 3021
Contact: firstname.lastname@example.org - 713-743-7451
Our long-term area of interest is to understand the molecular mechanisms of how cholesterol metabolites affect cardiovascular health and related diseases such as atherosclerosis, obesity, diabetes and cancer.
27-Hydroxycholesterol in Human Physiology through the Modulation of Estrogen Receptor Function
In addition to its role in reproduction, estrogen regulates many physiologic processes through the action by estrogen receptors (ER). Work in multiple animal models and observational clinical studies suggest that estrogen has the potential to provide potent cardiovascular protection, in contrast, the results of postmenopausal hormone replacement therapy to date are surprisingly negative in clinical trials. This raises the critically important and novel possibility that there are endogenous counterregulatory mechanisms.
Cholesterol is essential as a cellular membrane component and also for steroid hormone production, however, excess cholesterol causes adverse events such as atherosclerosis, or hardening of the arteries due to the buildup of cholesterol and other substances. Therefore, there are pathways to eliminate excess cholesterol as bile acids. Among cholesterol metabolites, 27-hydroxycholesterol (27HC) is the most abundant circulating oxysterol in the human body.
Previously, we discovered that 27HC binds to ER and acts as an endogenous inhibitor of ER action in the vasculature. It turned out that the effects by 27HC are tissue-specific, thus 27HC is the first identified endogenous selective estrogen receptor modulator, or SERM. The serum 27HC levels correlate well with cholesterol levels and also rise progressively with age. We have been investigating the pathophysiologic implications of the findings on the oxysterol in vitro and in vivo. We hope to develop a new therapeutic approach towards modulating 27HC levels to treat cholesterol- and/or estrogen receptor-mediated diseases such as cardiovascular diseases, bone weakening called osteoporosis, cancer and metabolic diseases.
1) Impact on Cardiovascular System
We found that in mice elevations in 27HC cause increased atherosclerosis independently from cholesterol; in addition, the protection of atherosclerosis development by estrogen is markedly suppressed by the effects of 27HC on both monocytes and vascular cells, which are the major components of atherosclerosis development. Thus, 27HC potently impairs the beneficial effects of estrogen on vascular function. Strategies to lower 27HC may complement existing approaches targeting cholesterol to prevent vascular disease.
Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, and Mangelsdorf DJ. (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 1185-1192.
Umetani M, Ghosh P, Ishikawa T, Umetani J, Ahmed M, Mineo C, Shaul PW. (2014) The Cholesterol Metabolite 27-Hydroxycholesterol Promotes Atherosclerosis via Proinflammatory Processes Mediated by Estrogen Receptor Alpha. Cell Metabolism. 20, 172-82.
2) Impact on Bone Mineralization
Estrogen also plays an important role in the regulation of bone mineralization, and estrogen deficiency caused by menopause or surgery results in pathological bone loss that can be reversed by estrogen replacement. On the other hand, higher level of circulating cholesterol called hypercholesterolemia is an independent risk factor for decreased bone mass in postmenopausal women, pointed to 27HC as a potential new modifier of bone mineralization. The administration of 27HC to female mice caused a decrease in bone mineral density (BMD) and decreased bone volume/total volume fraction. Although estrogen administration caused increases in BMD and bone thickness in control mice, the effects of estrogen were blocked with elevated 27HC levels. In addition, greater bone resorption, a breakdown of bone by osteoclasts, occurred in the mice with elevated 27HC levels. These findings indicate that 27HC has an adverse impact on bone mineralization, and that some of the effects of the oxysterol may be related to its activities as a SERM.
Dusell CD, Nelson, ER, Wang X, Abdo J, Mödder UI, Umetani M, Gesty-Palmer D, Javitt NB, Khosla S, and McDonnell DP. (2010) The Endogenous Selective Estrogen Receptor Modulator 27-Hydroxycholesterol Is a Negative Regulator of Bone Homeostasis. Endocrinol. 151, 3675-3685.
Nelson ER, DuSell CD, Wang X, Howe MK, Evans G, Michalek RD, Umetani M, Rathmell JC, Khosla S, Gesty-Palmer D, McDonnell DP. (2011) The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. Endocrinology 152, 4691-705.
3) Impact on Breast Cancer
Breast cancer is the most common malignancy in women other than skin cancer. Although estrogen is a well-known risk factor of ER-positive breast cancer, paradoxically postmenopausal women, who have decreased endogenous estrogen production, are particularly at increased risk of ER-positive breast cancer. This risk occurs at a time when circulating estrogen levels are declining, and endocrine-based therapies using synthetic SERMs or aromatase inhibition that blocks estrogen production are often ineffective or resistance develops, suggesting other important ER-mediated mechanisms. We found that 27HC is the first non-estrogen ER ligand that stimulates ER-positive breast tumor growth in cell culture and in vivo. As importantly, 27HC is overabundant in the microenvironment of ER-positive tumors in women. In addition, reduced expression of the 27HC-metabolizing enzyme in tumors, which increases local 27HC concentration in tumors, is associated with poorer survival of breast cancer patients. We are now conducting the mechanistic studies of the 27HC action in cancer cells and also try to develop a new approach to modulate local 27HC levels in the ER-positive tumors.
Dusell CD, Umetani M, Shaul PW, Mangelsdorf DJ, and McDonnell DP. (2008) 27-Hydroxycholesterol is an endogenous Selective Estrogen Receptor Modulator (SERM). Mol. Endocrinol. 22, 65-77.
Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B, Girard L, Mineo C, Brekken RA, Umetani M, Euhus DM, Xie Y, and Shaul PW. (2013) 27-Hydroxycholesterol Promotes Cell-autonomous ER-positive Breast Cancer Growth. Cell Reports. 5, 637-45.
Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J and McDonnell DP. (2013) 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology. Science. 342, 1094-8.
Physiological interaction between nuclear receptors LXRb and ERa
In vascular endothelial cells (EC) that line blood vessels, estrogen receptor (ER) induces endothelial nitric oxide synthase (eNOS) and maintains endothelial monolayer. The disruption of endothelial monolayer plays an integral role in the initiation of vascular dysfunction such as atherosclerosis. ER is a transcriptional factor and also has a nonnuclear action in the plasma membrane (PM), where ER participates in kinase-mediated signaling pathways. We found that ERα is also activated by nuclear receptor Liver X Receptor (LXR) in EC. The activation of LXRβ, the dominant isoform of LXR in EC, increases its direct binding to ERα in PM and initiates an extranuclear signaling cascade, which induces eNOS and protects endothelial monolayer integrity. LXR activation of NOS caused relaxation and stimulated healing of arteries from vascular injury via LXRβ- and ERα-dependent processes. These studies demonstrate that LXRβ has nonnuclear function in EC caveolae/lipid rafts that entails crosstalk with ERα. Our observations regarding mechanistic linkage between LXRβ and ERα have potential implications in cardiovascular health and disease and further support the concept that pharmacologic activation of LXRβ through its activation of ERα would be a promising new therapy against atherosclerosis and related diseases.
Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KL, Thomas GD, Mineo C, Yuhanna YS, Kim SH, Madak-Erdogan Z, Maggi A, Dineen SP, Roland CL, Hui DY, Brekken RA, Katzenellenbogen JA, Katzenellenbogen BS, and Shaul PW. (2010) Nongenomic Estrogen Receptor Alpha Signaling Promotes Cardiovascular Protection but not Uterine or Breast Cancer Growth in Mice. J. Clin. Invest. 120, 2319-2330.
Ishikawa T, Yuhanna IS, Umetani J, Lee WR, Korach KS, Shaul PW, and Umetani M*. (2013) LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488-97.
Michihisa Umetani, Ph.D.
Department of Biology and Biochemistry
University of Houston
Houston, Texas 77204-5001
Office: SERC 545, Room 3021
Postdoctoral Fellows & Researchers
Christine studied Cellular and Molecular Biology at Florida State University, and graduated cum laude and with Honors in 2007. During her time as an undergraduate, she developed an interest in transcription and the signaling mechanisms that connect environmental/lifestyle exposures to gene expression. She started graduate school at Louisiana State University in the Prufer-Stone laboratory studying Liver X Receptors (LXR). In her second year of graduate school, she transferred to the Burris laboratory, who then relocated to The Scripps Research Institute’s new campus in Jupiter, FL. She studied Retinoic Acid Receptor-Related Orphan Receptors (ROR) and Rev-erb Receptors as regulators of metabolism and circadian rhythms during her time at TSRI, and enjoyed the inter-disciplinary approach to drug discovery and translational research on campus. As postdoc, she studied cancer biology – Wnt-LGR signaling in lung cancer in the Liu laboratory at the University of Texas Health Science Center (UT-Health) and NR4A silencing in acute myeloid leukemia in the Conneely laboratory at Baylor College of Medicine.
Jose is a graduate student from Tamaulipas, Mexico. He came to the United States in 2009 and graduated from Texas A&M University with a degree in Biochemistry. Currently he is a Ph.D. Biochemistry student at UH. Jose hopes to learn more about the relationship of estrogen receptor in cholesterol and also hopes to learn more about cancer in Umetani Lab.
He is a graduate student in Cell and Molecular Biology at UH. He has completed his Bachelor's and Masters in Biotechnology at University of Tehran, Iran. Arvand has worked on metabolic network reconstruction of sperm cells in order to investigate sperm energy metabolism and its related diseases.
Nimra is an Undergraduate Intern pursuing a degree in Psychology with a minor in Biology on a pre-medical track. She is working in Dr. Umetani's lab on understanding cholesterol metabolites role in cardiovascular diseases. She hopes to gain knowledge, critical thinking skills, and the ability to use certain techniques through this opportunity as well as obtain experience that will assist in future endeavors in the health care field, academically and professionally. In her free time, she enjoys trying new foods, music, photography, and traveling.
Taylor is an undergraduate intern majoring in Biochemistry. He has aspirations of attending medical school and becoming a physician. When he is not working or studying, Taylor spends time pursuing a passion of photography and videography.
- Maroufy V, Shah P, Asghari A, Deng N, Ramirez JC, Yaseen A, Zheng WJ, Le RNU, Umetani M*, and Wu H*. (2020) Gene expression dynamic analysis reveals co-activation of Sonic Hedgehog and Epidermal Growth Factor followed by dynamic silencing. Oncotarget. 11, 1358-1372.
- Asghari A, Ishikawa T, Hiramitsu S, Lee WR, Umetani J, Bui L, Korach KS, and Umetani M*. (2019) 27-Hydroxycholesterol promotes adiposity and mimics adipogenic diet-induced inflammatory signaling. Endocrinology 160, 2485-2494. *Selected for the Thematic Issue of Cardiovascular Endocrinology 2020.
- Sirianni R, Umetani M and Pezzi V. (2019) Cholesterol and Oxysterols as Signal Molecules in Human Pathophysiology and Cancer. Front. Endocrinol. 10, 732.
- Wang YT, Chen J, Li X, Umetani M, Chen Y, Li PL, and Zhang Y. (2019) Contribution of Transcription Factor EB to AdipoRon-induced Inhibition of Arterial Smooth Muscle Cell Proliferation and Migration. Am. J. Physiol. Cell Physiol. 317, C1034-1047.
- Guan Y, Li X, Umetani M, Boini KM, Li PL, and Zhang Y. (2018) Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells. Basic Clin. Pharmacol. Toxicol. Doi: 10.1111/bcpt.13146.
- Lee J, Lee Y, LaVoy EC, Umetani M, Hong J, and Park Y. (2018) Physical activity protects NLRP3 inflammasome-associated coronary vascular dysfunction in obese mice. Physiol. Rep. 6, e13738.
- Hiramitsu S, Ishikawa T, Lee WR, Khan T, Crumbley C, Khwaja N, Zamanian F, Asghari A, Sen M, Zang Y, Hawse JR, Minna JD, and Umetani M. (2018) Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol. Front. Endocrinol. 9, 470-478. doi: 10.3389/fendo.2018.00470.
- Oguro H, McDonald JG, Zhao Z, Umetani M, Shaul PW, and Morrison SJ. (2017) 27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy. J. Clin. Invest. 127, 3392-3401.
- Chambliss KL, Barrera J, Umetani M, Umetani J, Kim SH, Madak-Erdogan Z, Huang L, Katzenellenbogen BS, Katzenellenbogen JA, Mineo C, and Shaul PW. (2016) Non-Nuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice. Endocrinology157, 3731-41.
- Umetani M*. (2016) Re-adopting classical nuclear receptors by cholesterol metabolites. J. Steroid BIochem. Mol. Biol. Doi: 10.1016/j.jsbmb.2015.11.002.
- Lee WR, Ishikawa T, and Umetani M*. (2014) The interaction between Metabolism, Cancer, and Cardiovascular disease, connected by 27-Hydroxycholesterol. Clin. Lipidol. 9, 617-24.
- Umetani M, Ghosh P, Ishikawa T, Umetani J, Ahmed M, Mineo C, Shaul PW. (2014) The Cholesterol Metabolite 27-Hydroxycholesterol Promotes Atherosclerosis via Proinflammatory Processes Mediated by Estrogen Receptor Alpha. Cell Metabolism. 20, 172-82.
- Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J and McDonnell DP. (2013) 27- Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology. Science. 342, 1094-8.
- Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B, Girard L, Mineo C, Brekken RA, Umetani M, Euhus DM, Xie Y, and Shaul PW. (2013) 27- Hydroxycholesterol Promotes Cell-autonomous ER-positive Breast Cancer Growth. Cell Reports. 5, 637-45.
- Ishikawa T, Yuhanna IS, Umetani J, Lee WR, Korach KS, Shaul PW, and Umetani M*. (2013) LXRb/estrogen receptor-a signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488-97.
- Umetani M* and Shaul PW*. (2011) 27-Hydroxycholesterol: the First Identified Endogenous SERM. Trends Endocrinol. Metab. 22, 130-5. (* corresponding authors)
- Nelson ER, DuSell CD, Wang X, Howe MK, Evans G, Michalek RD, Umetani M, Rathmell JC, Khosla S, Gesty-Palmer D, McDonnell DP. (2011) The oxysterol, 27- hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. Endocrinology 152, 4691-705.
- Li T, Holmstrom SR, Kir S, Umetani M, Schmidt DR, Kliewer SA, and Mangelsdorf DJ. (2011) The G Protein-Coupled Bile Acid Receptor, TGR5, Stimulates Gallbradder Filling. Mol. Endocrinol. 25, 1066-1071.
- Dusell CD, Nelson, ER, Wang X, Abdo J, Mödder UI, Umetani M, Gesty-Palmer D, Javitt NB, Khosla S, and McDonnell DP. (2010) The Endogenous Selective Estrogen Receptor Modulator 27-Hydroxycholesterol Is a Negative Regulator of Bone Homeostasis. Endocrinol. 151, 3675-3685.
- Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KL, Thomas GD, Mineo C, Yuhanna YS, Kim SH, Madak-Erdogan Z, Maggi A, Dineen SP, Roland CL, Hui DY, Brekken RA, Katzenellenbogen JA, Katzenellenbogen BS, and Shaul PW. (2010) Nongenomic Estrogen Receptor Alpha Signaling Promotes Cardiovascular Protection but not Uterine or Breast Cancer Growth in Mice. J. Clin. Invest. 120, 2319- 2330.
- Dusell CD, Umetani M, Shaul PW, Mangelsdorf DJ, and McDonnell DP. (2008) 27- Hydroxycholesterol is an endogenous Selective Estrogen Receptor Modulator (SERM). Mol. Endocrinol. 22, 65-77.
- Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, and Mangelsdorf DJ. (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 1185-1192.
- Horiuchi K*, Umetani M*, Minami T, Okayama H, Takada S, Yamamoto M, Aburatani H, Reid PC, Housman DE, Hamakubo T, and Kodama T. (2006) Wilms’ tumor 1- associating protein regulated G2/M transition through stabilization of cyclin A2 mRNA. Proc. Natl. Acad. Sci. USA 103, 17278-17283.
- Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, and Kliewer SA. (2006) Identification of a hormonal basis for gallbladder filling. Nat. Med. 12, 1253-1255.
- Yang C, McDonald JG, Patel A, Zhang Y, Umetani M, Xu F, Mangelsdorf DJ, Westover EJ, Covey DF, Cohen JC, and Hobbs HH. (2006) Sterol intermediates from cholesterol biosynthetic pathway as LXR ligands. J. Biol. Chem. 281, 27816-27826.
- Goodwin BJ, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, and Repa JJ. (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic receptor PXR. Proc. Natl. Acad. Sci. USA 100, 223-228.