scholarly journals Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryogo Furuhata ◽  
Yasuaki Kabe ◽  
Ayaka Kanai ◽  
Yuki Sugiura ◽  
Hitoshi Tsugawa ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Egf Receptor ◽  
De Novo ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Lipid Uptake ◽  
High Fat ◽  
Receptor Membrane

AbstractProgesterone receptor membrane associated component 1 (PGRMC1) exhibits haem-dependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. However, its physiological functions remain unknown. Herein, we demonstrate that PGRMC1 is required for adipogenesis, and its expression is significantly enhanced by insulin or thiazolidine, an agonist for PPARγ. The haem-dimerized PGRMC1 interacts with low-density lipoprotein receptors (VLDL-R and LDL-R) or GLUT4 to regulate their translocation to the plasma membrane, facilitating lipid uptake and accumulation, and de-novo fatty acid synthesis in adipocytes. These events are cancelled by CO through interfering with PGRMC1 dimerization. PGRMC1 expression in mouse adipose tissues is enhanced during obesity induced by a high fat diet. Furthermore, adipose tissue-specific PGRMC1 knockout in mice dramatically suppressed high-fat-diet induced adipocyte hypertrophy. Our results indicate a pivotal role of PGRMC1 in developing obesity through its metabolic regulation of lipids and carbohydrates in adipocytes.

scholarly journals Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3265
Author(s):  
Yasuaki Kabe ◽  
Ikko Koike ◽  
Tatsuya Yamamoto ◽  
Miwa Hirai ◽  
Ayaka Kanai ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Cancer Progression ◽  
Egf Receptor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Human Colon ◽  
Titration Calorimetry ◽  
Membrane Component ◽  
Human Colon Cancer ◽  
Receptor Membrane

Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.

scholarly journals Modification of fatty acid composition of polar and neutral lipids of blood and liver in rat in conditions of prolonged high-fat diet

2013 ◽  
Vol 59 (6) ◽  
pp. 644-654 ◽  
Author(s):  
T.P. Novgorodtseva ◽  
Yu.K. Karaman ◽  
N.V. Zhukova
Keyword(s):  
Fatty Acids ◽  
High Fat Diet ◽  
Prolonged Exposure ◽  
De Novo ◽  
Neutral Lipids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Fat ◽  
Lipid Fractions

Studied the composition of fatty acids of polar and neutral lipids of plasma, erythrocytes and liver Wistar rats under prolonged high-fat diet. It was established that during long-term (90-180 days) in rats high-fat load is blocking the cells ligand-retseptor active capture polyunsaturated fatty acids (PUFAs) in the low-density lipoprotein (LDL). This is confirmed by the accumulation of blood in LDL cholesterol and lipid fractions, esterified n-3 and n-6 PUFA (triacylglycerides, sterols esters, phospholipids), while the deficit these same fatty acids in the lipids of erythrocytes. In the liver under the influence of prolonged high-fat diet increased pool monoenic (18:1 n-9) and polyunsaturated (20:5 n-3, 20:3 n-6, 22:5 n-3) fatty acids. These data suggest that prolonged exposure of rats high-fat diet contributes to compensatory de novo synthesis of fatty acids in the liver. However, due to violations of the receptor active transport of fatty acids synthesized in the liver fatty acids are not captured by cells of the peripheral organs. Identified data allow us to expand the understanding of the role of nutritional factors in the physiology and pathophysiology of the cell, modulation of lipid metabolism.

scholarly journals Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

2021 ◽  
Author(s):  
P. Comeglio ◽  
E. Sarchielli ◽  
S. Filippi ◽  
I. Cellai ◽  
G. Guarnieri ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Therapeutic Potential ◽  
Rabbit Model ◽  
Free Testosterone ◽  
Preclinical Model ◽  
High Fat ◽  
Liver Health ◽  
Metabolic Dysfunctions

Abstract Purpose Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. Methods Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. Results Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. Conclusions Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

scholarly journals High-fat diet-induced obesity and impairment of brain neurotransmitter pool

2020 ◽  
Vol 11 (1) ◽  
pp. 147-160
Author(s):  
Ranyah Shaker M. Labban ◽  
Hanan Alfawaz ◽  
Ahmed T. Almnaizel ◽  
Wail M. Hassan ◽  
Ramesa Shafi Bhat ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Tissue ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
Obese Group ◽  
Control Group ◽  
High Fat ◽  
Brain Neurotransmitter ◽  
The Brain ◽  
Lean Group

AbstractObesity and the brain are linked since the brain can control the weight of the body through its neurotransmitters. The aim of the present study was to investigate the effect of high-fat diet (HFD)-induced obesity on brain functioning through the measurement of brain glutamate, dopamine, and serotonin metabolic pools. In the present study, two groups of rats served as subjects. Group 1 was fed a normal diet and named as the lean group. Group 2 was fed an HFD for 4 weeks and named as the obese group. Markers of oxidative stress (malondialdehyde, glutathione, glutathione-s-transferase, and vitamin C), inflammatory cytokines (interleukin [IL]-6 and IL-12), and leptin along with a lipid profile (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels) were measured in the serum. Neurotransmitters dopamine, serotonin, and glutamate were measured in brain tissue. Fecal samples were collected for observing changes in gut flora. In brain tissue, significantly high levels of dopamine and glutamate as well as significantly low levels of serotonin were found in the obese group compared to those in the lean group (P > 0.001) and were discussed in relation to the biochemical profile in the serum. It was also noted that the HFD affected bacterial gut composition in comparison to the control group with gram-positive cocci dominance in the control group compared to obese. The results of the present study confirm that obesity is linked to inflammation, oxidative stress, dyslipidemic processes, and altered brain neurotransmitter levels that can cause obesity-related neuropsychiatric complications.

scholarly journals Effect of Soybean and Soybean Koji on Obesity and Dyslipidemia in Rats Fed a High-Fat Diet: A Comparative Study

2021 ◽  
Vol 18 (11) ◽  
pp. 6032
Author(s):  
Sihoon Park ◽  
Jae-Joon Lee ◽  
Hye-Won Shin ◽  
Sunyoon Jung ◽  
Jung-Heun Ha
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Unsaturated Fatty Acids ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Lipoprotein Cholesterol ◽  
Health Concern ◽  
High Fat ◽  
Cholesterol Levels

Soybean koji refers to steamed soybeans inoculated with microbial species. Soybean fermentation improves the health benefits of soybeans. Obesity is a serious health concern owing to its increasing incidence rate and high association with other metabolic diseases. Therefore, we investigated the effects of soybean and soybean koji on high-fat diet-induced obesity in rats. Five-week-old male Sprague-Dawley rats were randomly divided into four groups (n = 8/group) as follows: (1) regular diet (RD), (2) high-fat diet (HFD), (3) HFD + steamed soybean (HFD+SS), and (4) HFD + soybean koji (HFD+SK). SK contained more free amino acids and unsaturated fatty acids than SS. In a rat model of obesity, SK consumption significantly alleviated the increase in weight of white adipose tissue and mRNA expression of lipogenic genes, whereas SS consumption did not. Both SS and SK reduced serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels. SS and SK also inhibited lipid accumulation in the liver and white adipose tissue and reduced adipocyte size. Although both SS and SK could alleviate HFD-induced dyslipidemia, SK has better anti-obesity effects than SS by regulating lipogenesis. Overall, SK is an excellent functional food that may prevent obesity.

Triterpenoid-Rich Fraction from Ilex hainanensis Merr. Attenuates Non-Alcoholic Fatty Liver Disease Induced by High Fat Diet in Rats

2013 ◽  
Vol 41 (03) ◽  
pp. 487-502 ◽  
Author(s):  
Wei-Xi Cui ◽  
Jie Yang ◽  
Xiao-Qing Chen ◽  
Qian Mao ◽  
Xiang-Lan Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Liver Disease ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Density Lipoprotein ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Cyp2e1 Expression ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) has become a major challenge to the healthcare system. This study was designed to evaluate the effect of the triterpenoid-rich fraction (TF) from Ilex hainanensis Merr. on NAFLD. Male Sprague-Dawley (SD) rats were fed a normal diet (control) or high fat diet (NAFLD model). After four weeks, the high fat diet group was orally administrated TF (250 mg/kg) for another two weeks. High fat diet fed rats displayed hyperlipidemia and a decline in liver function compared with control. However, administration with TF could effectively improve these symptoms, as demonstrated by decreasing the plasma levels of triglyceride (p <0.05), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.05), alanine transaminase (p < 0.05), aspartate aminotransferase (p < 0.01), liver index (p < 0.05) and insulin resistance index (p < 0.05) while increasing the high-density lipoprotein cholesterol (p < 0.05). Meanwhile, histopathological examination of livers also showed that TF could reduce the incidence of liver lesions induced by high fat diet. Furthermore, TF could alleviate oxidative stress and inflammation status indicated by the decline malondialdehyde and superoxide dismutase levels (p < 0.01, both) and levels of interleukin 6 and tumor necrosis factor-α (p < 0.05). In addition, immunohistochemistry showed TF evidently elevated the peroxisome proliferator-activated receptor (PPARα) expression (p < 0.01), while it diminished the Cytochrome P450 2E1 (CYP2E1) expression (p < 0.01) in liver. These results demonstrate that TF has potential ability to protect liver against NAFLD by regulating lipids metabolism and alleviating insulin resistance, inflammation and oxidative stress. This effect might be associated with regulating PPARα and CYP2E1 expression.

Abstract 58: Angiotensin-(1-7) Mas Receptors In The Arcuate Nucleus Of The Hypothalamus Protect Against High Fat Diet-induced Insulin Resistance In Female Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Darren Mehay ◽  
Sarah Bingaman ◽  
Yuval Silberman ◽  
Amy Arnold
Keyword(s):  
Body Composition ◽  
Insulin Sensitivity ◽  
Energy Balance ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Arcuate Nucleus ◽  
Control Diet ◽  
High Fat ◽  
Metabolic Outcomes

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that improves insulin sensitivity, glucose tolerance, and energy balance in obese rodents. Our recent findings suggest that Ang-(1-7) activates mas receptors (MasR) in the arcuate nucleus of the hypothalamus (ARC), a brain region critical to control of energy balance and glucose homeostasis, to induce these positive metabolic effects. The distribution of MasR in the ARC and their role in metabolic regulation, however, is unknown. We hypothesized: (1) MasR are expressed in the ARC; and (2) deletion of ARC MasR leads to worsened metabolic outcomes following high fat diet (HFD). To test this, male and female C57Bl/6J mice were fed a 60% HFD or matched control diet ad libitum for 12 weeks. RNAscope in situ hybridization was performed on coronal ARC sections in rostral-middle-caudal regions to determine percentage of MasR positive neurons (n=5/group). In a second experiment, we assessed body composition and insulin and glucose tolerance in transgenic mice with deletion of MasR in ARC neurons (MasR-flox with AAV5-hsyn-GFP-Cre). RNAscope revealed a wide distribution on MasR-positive cells throughout the rostral to caudal extent of the ARC. The average percentage of MasR positive neurons was increased in females versus males, with HFD tending to increase MasR expression in both sexes (control diet male: 11±2; control diet female: 17±3; HFD male: 15±5; HFD female: 24±2; p sex : 0.030; p diet : 0.066; p int : 0.615; two-way ANOVA). Deletion of MasR in ARC neurons worsened insulin sensitivity in HFD but not control diet females (area under the curve for change in glucose from baseline: -1989±1359 HFD control virus vs. 2530±1762 HFD Cre virus; p=0.016), while fasting glucose, glucose tolerance, and body composition did not change. There was no effect of ARC MasR deletion on metabolic outcomes in control diet or HFD male mice. These findings suggest females have more MasR positive neurons in the ARC compared to males, which may be a sex-specific protective mechanism for glucose homeostasis. While further studies are needed to explore the role of ARC MasR in metabolic regulation, these findings support targeting Ang-(1-7) as an innovative strategy in obesity.

Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet

2005 ◽  
Vol 289 (2) ◽  
pp. G300-G307 ◽  
Author(s):  
Robert P. Erickson ◽  
Achyut Bhattacharyya ◽  
Robert J. Hunter ◽  
Randall A. Heidenreich ◽  
Nathan J. Cherrington
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
Cholestatic Hepatitis ◽  
Diffuse Fibrosis ◽  
Acid Transport ◽  
High Fat ◽  
Bile Acid Transport ◽  
Niemann Pick

Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1−/− mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol (“high-fat”) diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1–5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1−/− mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1−/− mice on the high-fat diet; it was massively increased in the Ldlr−/− mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. γ-Glutamyltransferase was also elevated in Npc1−/− mice, more so on the high-fat diet. Mrps 1–5 were elevated in Npc1−/− liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1−/− liver and were suppressed by the high-fat diet. In conclusion, Npc1−/− mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.

scholarly journals 7-Hydroxymatairesinol improves body weight, fat and sugar metabolism in C57BJ/6 mice on a high-fat diet

2018 ◽  
Vol 120 (7) ◽  
pp. 751-762 ◽  
Author(s):  
Giorgio Biasiotto ◽  
Isabella Zanella ◽  
Federica Predolini ◽  
Ivonne Archetti ◽  
Moris Cadei ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Body Weight ◽  
High Fat Diet ◽  
Sugar Metabolism ◽  
Lipid Uptake ◽  
High Fat ◽  
Total Extract ◽  
The Metabolic Syndrome ◽  
Metabolic Genes

Abstract7-Hydroxymatairesinol (7-HMR) is a plant lignan abundant in various concentrations in plant foods. The objective of this study was to test HMRLignan™, a purified form of 7-HMR, and the correspondingPicea abiesextract (total extractP. abies; TEP) as dietary supplements on a background of a high-fat diet (HFD)-induced metabolic syndrome in mice and in the 3T3-L1 adipogenesis model. Mice, 3 weeks old, were fed a HFD for 60 d. Subgroups were treated with 3 mg/kg body weight 7-HMR (HMRLignan™) or 10 mg/kg body weight TEP by oral administration. 7-HMR and TEP limited the increase in body weight (−11 and −13 %) and fat mass (−11 and −18 %) in the HFD-fed mice. Epididymal adipocytes were 19 and −12 % smaller and the liver was less steatotic (−62 and −65 %). Serum lipids decreased in TEP-treated mice (−11 % cholesterol, −23 % LDL and −15 % TAG) and sugar metabolism was ameliorated by both lignan preparations, as shown by a more than 70 % decrease in insulin secretion and insulin resistance. The expression of several metabolic genes was modulated by the HFD with an effect that was reversed by lignan. In 3T3-L1 cells, the 7-HMR metabolites enterolactone (ENL) and enterodiol (END) showed a 40 % inhibition of cell differentiation accompanied by the inhibited expression of the adipogenic genesPPARγ,C/EBPαandaP2. Furthermore, END and ENL caused a 10 % reduction in TAG uptake in HEPA 1–6 hepatoma cells. In conclusion, 7-HMR and TEP reduce metabolic imbalances typical of the metabolic syndrome and obesity in male mice, whereas their metabolites inhibit adipogenesis and lipid uptakein vitro.

scholarly journals A 12-week low-carbohydrate, high-fat diet improves metabolic health outcomes over a control diet in a randomised controlled trial with overweight defence force personnel

2017 ◽  
Vol 42 (11) ◽  
pp. 1158-1164 ◽  
Author(s):  
Caryn Zinn ◽  
Julia McPhee ◽  
Nigel Harris ◽  
Micalla Williden ◽  
Kate Prendergast ◽  
...  
Keyword(s):  
Health Outcomes ◽  
High Fat Diet ◽  
Controlled Trial ◽  
Intervention Group ◽  
Density Lipoprotein ◽  
Metabolic Health ◽  
High Fat ◽  
Beneficial Effects ◽  
Low Carbohydrate ◽  
Randomised Controlled

Overweight, obesity, and poor health is becoming a global concern for defence force personnel. Conventional nutrition guidelines are being questioned for their efficacy in achieving optimal body composition and long-term health. This study compared the effects of a 12-week low-carbohydrate, high-fat diet with a conventional, high-carbohydrate, low-fat diet on weight reduction and metabolic health outcomes in at-risk New Zealand Defence Force personnel. In this randomised controlled trial, 41 overweight personnel were assigned to intervention and control groups. Weight, waist circumference, fasting lipids, and glycaemic control were assessed at baseline and at 12 weeks. Within-group change scores were analysed using the t statistic and interpreted using a p < 0.05 level of statistical significance. Between-group mean differences and confidence intervals were analysed using effect sizes and magnitude-based inferences. Twenty-six participants completed the trial (14 intervention, 12 control). Both groups showed statistically significant weight and waist circumference reductions; the intervention group significantly reduced triglycerides and serum glucose and significantly increased high-density lipoprotein cholesterol (HDLc). Relative to control, the intervention group showed small, possibly to likely beneficial effects for weight, triglycerides, glucose, insulin, and homeostasis model assessment of insulin resistance; moderate, likely beneficial effects for HDL cholesterol, triglyceride:HDLc ratio and HbA1c; and a small, likely harmful effect for low-density lipoprotein cholesterol. This dietary approach shows promise for short-term weight loss and improved metabolic health outcomes conditions compared with mainstream recommendations. It should be offered to defence force personnel at least as a viable alternative means to manage their weight and health.

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