Krüppel-like Factor-9 and Krüppel-like Factor-13: Highly Related, Multi-Functional, Transcriptional Repressors and Activators of Oncogenesis.

Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes.

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice.

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet.

Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet.

Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female (wild type, WT) and (knockout, KO) mice were fed HFD (beginning at age 35 days) for 12 weeks, after which liver and adipose tissues were obtained, and serum adiponectin and leptin levels, liver fat content, and markers of oxidative stress evaluated.

Lesion Genotype Modifies High-Fat Diet Effects on Endometriosis Development in Mice.

Endometriosis is a chronic, estrogen-dependent gynecologic disorder that affects reproductive-aged women and to a lesser extent, post-menopausal women on hormone therapy. The condition is associated with systemic and local immune dysfunctions. While its underlying mechanisms remain poorly understood, endometriosis has a genetic component and propensity for the disease is subject to environmental, nutritional, and lifestyle influences.

Breast adipose regulation of premenopausal breast epithelial phenotype involves interleukin 10.

Epidemiological studies inversely associate BMI with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the 'local' environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI = 27 kg/m2) and obese (mean BMI = 44 kg/m2) women.

Malic enzyme 1 (ME1) in the biology of cancer: it is not just intermediary metabolism.

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine.

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells.

Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy.

Complex epigenetic patterns in cerebellum generated after developmental exposure to trichloroethylene and/or high fat diet in autoimmune-prone mice.

Trichloroethylene (TCE) is an environmental contaminant associated with immune-mediated inflammatory disorders and neurotoxicity. Based on known negative effects of developmental overnutrition on neurodevelopment, we hypothesized that developmental exposure to high fat diet (HFD) consisting of 40% kcal fat would enhance neurotoxicity of low-level (6 μg per kg per day) TCE exposure in offspring over either stressor alone. Male offspring were evaluated at ∼6 weeks of age after exposure beginning 4 weeks preconception in the dams until weaning.

Malic Enzyme 1 (ME1) is pro-oncogenic in Apc mice.

Cytosolic Malic Enzyme (ME1) provides reduced NADP for anabolism and maintenance of redox status. To examine the role of ME1 in tumor genesis of the gastrointestinal tract, we crossed mice having augmented intestinal epithelial expression of ME1 (ME1-Tg mice) with Apc mice to obtain male Apc/ME1-Tg mice. ME1 protein levels were significantly greater within gut epithelium and adenomas of male Apc/ME1-Tg than Apc mice.

Notch-1 Signaling Activation and Progesterone Receptor Expression in Ectopic Lesions of Women With Endometriosis.

Context: Progesterone (P) resistance is a hallmark of endometriosis, but the underlying mechanism(s) for loss of P sensitivity leading to lesion establishment remains poorly understood.

Objective: To evaluate the association between Notch-1 signaling activation and P resistance in the progression of endometriosis.

Design: Case control study; archived formalin-fixed, paraffin-embedded tissues.

Opposing Actions of Developmental Trichloroethylene and High-Fat Diet Coexposure on Markers of Lipogenesis and Inflammation in Autoimmune-Prone Mice.

Trichloroethylene (TCE) is a widespread environmental pollutant associated with immunotoxicity and autoimmune disease. Previous studies showed that mice exposed from gestation through early life demonstrated CD4+ T cell alterations and autoimmune hepatitis. Determining the role of one environmental risk factor for any disease is complicated by the presence of other stressors.

Diets Containing Shiitake Mushroom Reduce Serum Lipids and Serum Lipophilic Antioxidant Capacity in Rats.

Background: We previously reported that dietary intake of shiitake mushroom (SM; Lentinus edodes) decreased serum concentrations of polar lipids in male rats.

Objective: This study evaluated the dietary effects of SM on serum cholesterol-related and serum antioxidant indexes in rats of both sexes.

Methods: Sprague-Dawley rats [38 dams and their offspring (20 males and 20 females/diet)] were fed diets containing 0 (control), 1%, 4%, or 10% (wt:wt) SM powder from gestation day 4 through to postnatal day (PND) 126.

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice.

The emerging links between breast cancer and metabolic dysfunctions brought forth by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status that affects the disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well defined.

High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status.

Endometriosis is a benign gynecological condition that causes considerable morbidity due to associated infertility, debilitating pelvic pain and inflammatory dysfunctions. Diet is a highly modifiable risk factor for many chronic diseases, but its contribution to endometriosis has not been extensively investigated, due partly to the paradoxical inverse association between obesity and disease incidence. Nevertheless, chronic exposure to dietary high-fat intake has been linked to greater systemic inflammation and oxidative stress, both features of women with endometriosis.

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells.

Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we determined the effects of soybean-derived bioactive molecules and the anti-diabetes drug metformin (MET), alone and together, on the growth, survival, and frequency of CSC in human HCT116 cells.

Krüppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling.

Unlabelled: Expression of the transcription factor Krüppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc (Min/+) mouse and compared their adenoma burdens at 16 weeks of age. While small intestine adenoma burden remained unchanged among Klf9 genotypes, male and female Apc(Min/+)/Klf9(-/-) and Apc(Min/+)/Klf9(+/-) mice exhibited significantly more colon adenomas than their Apc(Min/+)/Klf9(+/+) counterparts.

Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.

Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined.

Enhanced gastrointestinal expression of cytosolic malic enzyme (ME1) induces intestinal and liver lipogenic gene expression and intestinal cell proliferation in mice.

The small intestine participates in lipid digestion, metabolism and transport. Cytosolic malic enzyme 1 (ME1) is an enzyme that generates NADPH used in fatty acid and cholesterol biosynthesis. Previous work has correlated liver and adipose ME1 expression with susceptibility to obesity and diabetes; however, the contributions of intestine-expressed ME1 to these conditions are unknown.

Prolonged pregnancy in women is associated with attenuated myometrial expression of progesterone receptor co-regulator Krüppel-like Factor 9.

Context: Late-term pregnancy may lead to maternal and neonatal morbidity and mortality. Mice null for the progesterone receptor co-regulator Krüppel-like Factor 9 (KLF9) exhibit delayed parturition and increased incidence of neonatal deaths.

Objective: Our aim is to evaluate the contribution of myometrial KLF9 to human parturition.

Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning.

Krüppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis.

Endometriosis, a steroid hormone-dependent disease characterized by aberrant activation of estrogen receptor signaling and progesterone resistance, remains intractable because of the complexity of the pathways underlying its manifestation. We previously showed that eutopic endometria of women with endometriosis exhibit lower expression of Krüppel-like factor 9 (KLF9), a progesterone receptor coregulator in the uterus, relative to that of women without disease. Here we examined whether loss of endometrial KLF9 expression causes ectopic lesion establishment using syngeneic wild-type (WT) mice as recipients of endometrial fragments from WT and Klf9 null donors.

The role of thyroid hormone signaling in the prevention of digestive system cancers.

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues.

Suppression of Wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming.

Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. In this study, we investigated whether early exposure to blueberry (BB) via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein (CAS, control) or blueberry-supplemented (CAS + 3%BB) diets throughout pregnancy and lactation.

Cytosolic malic enzyme 1 (ME1) mediates high fat diet-induced adiposity, endocrine profile, and gastrointestinal tract proliferation-associated biomarkers in male mice.

Background: Obesity and associated hormonal disturbances are risk factors for colon cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used for lipogenesis in gastrointestinal (GI), liver and adipose tissues. We have reported that inclusion of soy protein isolate (SPI) in the diet lowered body fat content and colon tumor incidence of rats fed AIN-93G diet, while others have demonstrated SPI inhibition of rat hepatic ME1 expression.

The reproductive phenotype of mice null for transcription factor Krüppel-like factor 13 suggests compensatory function of family member Krüppel-like factor 9 in the peri-implantation uterus.

The ovarian hormones estrogen and progesterone promote uterine receptivity and successful pregnancy through their cognate receptors functioning in concert with context-dependent nuclear coregulators. Previously, we showed that the transcription factor Krüppel-like factor (KLF) 9 is a progesterone receptor (PGR) coactivator in the uterus and that mice null for Klf9 exhibit subfertility and reduced progesterone sensitivity. The highly related family member KLF13 displays increased expression in uteri of pregnant and nonpregnant Klf9 null mice and similarly regulates PGR-mediated transactivation in endometrial stromal cells.