Pgc1a is responsible for the sex differences in hepatic Cidec/Fsp27β mRNA expression in hepatic steatosis of mice fed a Western diet

Hepatic fat-specific protein 27 [cell death-inducing DNA fragmentation effector protein C ( Cidec)/ Fsp27] mRNA levels have been associated with hepatic lipid droplet extent under certain circumstances. To address its hepatic expression under different dietary conditions and in both sexes, apolipoprotein E ( Apoe) -deficient mice were subjected to different experimental conditions for 11 wk to test the influence of cholesterol, Western diet, squalene, oleanolic acid, sex, and surgical castration on Cidec/Fsp27 mRNA expression. Dietary cholesterol increased hepatic Cidec/Fsp27β expression, an effect that was suppressed when cholesterol was combined with saturated fat as represented by Western diet feeding. Using the latter diet, neither oleanolic acid nor squalene modified its expression. Females showed lower levels of hepatic Cidec/Fsp27β expression than males when they were fed Western diets, a result that was translated into a lesser amount of CIDEC/FSP27 protein in lipid droplets and microsomes. This was also confirmed in low-density lipoprotein receptor ( Ldlr)-deficient mice. Incubation with estradiol resulted in decreased Cidec/Fsp27β expression in AML12 cells. Whereas male surgical castration did not modify the expression, ovariectomized females did show increased levels compared with control females. Females also showed increased expression of peroxisome proliferator-activated receptor-γ coactivator 1-α ( Pgc1a), suppressed by ovariectomy, and the values were significantly and inversely associated with those of Cidec/Fsp27β. When Pgc1a-deficient mice were used, the sex differences in Cidec/Fsp27β expression disappeared. Therefore, hepatic Cidec/Fsp27β expression has a complex regulation influenced by diet and sex hormonal milieu. The mRNA sex differences are controlled by Pgc1a.

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Molecular Pathology of Müller’s Muscle in Graves’ Ophthalmopathy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-1877 ◽

2006 ◽

Vol 91 (3) ◽

pp. 1159-1167 ◽

Cited By ~ 25

Author(s):

Mei-Ju Shih ◽

Shu-Lang Liao ◽

Kuan-Ting Kuo ◽

Terry J. Smith ◽

Lee-Ming Chuang

Keyword(s):

Mrna Expression ◽

Molecular Pathology ◽

Disease Process ◽

Clinical Severity ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Histological Changes ◽

Peroxisome Proliferator Activated Receptor ◽

Graves Ophthalmopathy ◽

Upper Lid

Abstract Context: Upper lid retraction is a common sign in Graves’ ophthalmopathy (GO). Whether Müller’s muscle is involved in upper lid retraction has not been fully elucidated. Objective: The objective of the study was to understand the molecular pathology of Müller’s muscle in GO. Design/Setting/Participants: A method for measurement of histological changes was developed and used to correlate severity and expression of cell-specific genes in GO. Main Outcome Measures: Histological changes, clinical severity of upper lid retraction, and mRNA expression in Müller’s muscle in GO were measured. Results: The degree of fibrosis correlates with severity of upper lid retraction. Macrophage infiltration was increased in fibrotic areas, consistent with higher levels of macrophage-colony stimulating factor mRNA. Levels of peroxisome proliferator-activated receptor-γ mRNA were up-regulated and correlated with fat infiltration. Decreased muscle mass correlated with lower myocardin mRNA expression. The expression of c-kit levels was decreased in diseased muscles, consistent with diminished mast cell numbers. Conclusion: The pathological changes of Müller’s muscle correlate with clinical severity of upper lid retraction in GO. Patterns of gene expression appear to correlate with the histopathological changes in this disease process.

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Acyloxyacyl Hydrolase Modulates the Gut Microbiome Through Transcriptional Regulators of Corticotropin-Releasing Factor

10.1101/2021.03.04.433950 ◽

2021 ◽

Author(s):

Afrida Rahman-Enyart ◽

Lizath M. Aguiniga ◽

Wenbin Yang ◽

Ryan E. Yaggie ◽

Bryan White ◽

...

Keyword(s):

Sex Differences ◽

Pelvic Pain ◽

Gut Microbiome ◽

Transcriptional Regulators ◽

Corticotropin Releasing Factor ◽

Conditional Knockout ◽

Peroxisome Proliferator ◽

Bladder Pain ◽

Acyloxyacyl Hydrolase ◽

Deficient Mice

ABSTRACTGut microbiome-host interactions play a crucial role in health and disease. Altered gut microbiome composition has been observed in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), a disorder characterized by pelvic pain, voiding dysfunction, and often co-morbid with anxiety/depression. We recently showed that mice deficient for acyloxyacyl hydrolase (AOAH) mimic pelvic pain symptoms and comorbidities of IC/BPS and also exhibit gut dysbiosis. In addition, we previously identified that the conditional knockout (cKO) of two transcriptional regulators of the gene encoding corticotropin-releasing factor, Crf, that are downstream of AOAH, aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ (PPARγ), alleviate anxiety/depressive and voiding phenotypes of AOAH-deficient mice. Here, we examined the effects of AhR and PPARγ in CRF-expressing cells on the dysbiosis of AOAH-deficiency. AOAH-deficient mice with cKO of PPARγ and AhR/PPARγ exhibited reduced pelvic allodynia compared to AOAH-deficient mice, suggesting a role for PPARγ in regulating pelvic pain. 16S rRNA sequencing of fecal stool from female AOAH-deficient mice with a cKO of AhR and/or PPARγ in CRF-expressing cells identified altered gut microbiota distinct from AOAH-deficient stool. The cKO of AhR and PPARγ showed improved cecum barrier function in females compared to AOAH-deficient mice, whereas males were primarily affected by PPARγ, suggesting sex differences in gut responses. Pair-wise comparison of microbiota also suggested sex differences in response to AOAH-deficiency and conditional knockout of AhR and PPARγ. Our findings suggest that the dysbiosis and leaky gut of AOAH deficiency is mediated by AhR and PPARγ in CRF-expressing cells and reveal a novel mechanism and therapeutic targets for pelvic pain.

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The effect of omega3 fatty acid supplementation on PPARγ and UCP2 expressions, resting energy expenditure, and appetite in athletes

BMC Sports Science Medicine and Rehabilitation ◽

10.1186/s13102-021-00266-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Sara Moradi ◽

Mohamadreza Alivand ◽

Yaser KhajeBishak ◽

Mohamad AsghariJafarabadi ◽

Maedeh Alipour ◽

...

Keyword(s):

Energy Expenditure ◽

Mrna Expression ◽

Resting Energy Expenditure ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Double Blind ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Ucp2 Mrna ◽

Resting Energy

Abstract Background Omega3 fatty acids as a ligand of energy-related genes, have a role in metabolism, and energy expenditure. These effects are due to changes in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and uncoupling protein2 (UCP2). This study evaluated the effect of omega3 supplements on PPARγ mRNA expression and UCP2 mRNA expression and protein levels, as regulators of energy metabolism, resting energy expenditure (REE), and appetite in athletes. Methods In a 3-week double-blind RCT in Tabriz, Iran, in 2019, 36 male athletes, age 21.86 (±3.15) y with 16.17 (±5.96)% body fat were randomized to either an intervention (2000 mg/day omega3; EPA: 360, DHA: 240) or placebo (2000 mg/day edible paraffin) groups. Appetite and REE were assessed before and after the intervention. PPARγ and UCP2 mRNA expression and UCP2 protein levels in blood were evaluated by standard methods. Results Results showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05). Conclusions Our findings showed that omega3 supplementation leads to the up-regulation of PPARγ and UCP2 expressions as the indicators of metabolism in healthy athletes.

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Evidence for an Alternative Mechanism Suppressing Hepcidin during the Recovery from Hemorrhage-Induced Anemia

Blood ◽

10.1182/blood-2018-99-118647 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1047-1047

Author(s):

Ugo Sardo ◽

Prunelle Perrier ◽

Benjamin Billore ◽

Kevin Cormier ◽

Leon C. Kautz

Keyword(s):

Mrna Expression ◽

Target Genes ◽

Conflicts Of Interest ◽

The Body ◽

Alternative Mechanism ◽

Hepatic Expression ◽

Protein Levels ◽

Stress Erythropoiesis ◽

Hepcidin Mrna ◽

Deficient Mice

Abstract Introduction The liver-produced hormone hepcidin regulates the body iron stores. Its expression is induced by iron and inflammatory cytokines but repressed by the erythroid regulator erythroferrone (ERFE) when erythropoietic activity intensifies during anemia. Although Erfe-deficient mice fail to appropriately suppress hepcidin during the first 24h following hemorrhage, these mice still recover from anemia with a few days delay suggesting that another mechanism compensates for the absence of ERFE. We therefore decided to study the kinetic of hepcidin during the recovery from anemia induced by bleeding in Erfe-deficient mice. Material and methods Six week-old C57BL/6 WT and Erfe-deficient mice were phlebotomized (500 μL) and analyzed 1, 2, 3, 4, 5 and 6 days after phlebotomy until full recovery. Results Liver hepcidin mRNA expression was suppressed 5-fold one to five days after phlebotomy in WT mice. In contrast with the sustained inhibition of hepcidin, serum ERFE concentration progressively decreased after 24 hours to reach its baseline at day 4. Interestingly, although hepcidin levels were unchanged after 24 hours, Erfe-deficient exhibited significantly reduced hepcidin levels after 48 hours. Hepcidin mRNA and protein levels were comparable to those of WT mice 2 to 5 days after phlebotomy. Interestingly, the repression of hepcidin occurred without any change in phosphorylation of the effectors Smadd1/5/8 and in hepatic expression of the BMP/SMAD target genes Atoh8, Smad7 and Id1. Similarly, mRNA expression of the proposed negative regulators of hepcidin Gdf15, Twsg1 and Gdf11 was not increased in the spleen and the bone marrow of phlebotomized mice compared to control mice. Finally, disruption of the erythroid compartment by irradiation or injection of carboplatin prevented the suppression of hepcidin in WT and Erfe-deficient mice. Conclusion An alternative mechanism regulates hepcidin independently of iron and ERFE during stress erythropoiesis. Our data suggest that a second yet unknown erythroid regulator of hepcidin may exist. Disclosures No relevant conflicts of interest to declare.

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The peroxisome-proliferator-activated receptor alpha agonist ciprofibrate severely aggravates hypercholesterolaemia and accelerates the development of atherosclerosis in mice lacking apolipoprotein E

Biochemical Journal ◽

10.1042/bj20030105 ◽

2003 ◽

Vol 373 (3) ◽

pp. 941-947 ◽

Cited By ~ 33

Author(s):

Tao FU ◽

Papreddy KASHIREDDY ◽

Jayme BORENSZTAJN

Keyword(s):

Apolipoprotein E ◽

Plasma Cholesterol ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Very Low Density Lipoproteins ◽

Peroxisome Proliferator Activated Receptor ◽

Atherosclerotic Lesions ◽

Deficient Mice

Mice lacking apolipoprotein E (apoE) are characterized by severe hypercholesterolaemia, caused by an abnormal accumulation of apolipoprotein B-48 (apoB-48)-carrying remnants of chylomicrons and very-low-density lipoproteins (VLDL) in the plasma, and by the spontaneous development of atherosclerotic lesions. Ciprofibrate is a hypolipidaemic compound that acts primarily by enhancing the oxidation of fatty acids in the liver and, consequently, decreasing the production of hepatic VLDL. In the present study, homozygous apoE-deficient mice were fed with a normal chow diet, supplemented with ciprofibrate. We report that, as anticipated, ciprofibrate treatment (a) stimulated hepatic fatty acid oxidation, as indicated by an increase in the mRNA levels of peroxisomal fatty acyl-CoA oxidase (AOX) and peroxisomal bifunctional enzyme, and (b) decreased the hepatic secretion of VLDL into the plasma, as determined by treating the animals with Triton WR-1339. Paradoxically, the apoE-deficient mice developed a 3–4-fold increase in their plasma cholesterol levels. A similar effect was observed in apoE-deficient mice treated with other peroxisome-proliferator-activated receptor α agonists (fenofibrate, bezafibrate and WY14,643). By FPLC of the plasma and Western-blot analysis, we determined that the enhanced hypercholesterolaemia was due to an increased accumulation of apoB-48-carrying lipoprotein remnants in the plasma. Consistent with this finding, atherosclerotic lesions in animals treated with ciprofibrate for 90 days were considerably more advanced than in untreated animals. These results indicate that the ciprofibrate-induced accumulation of apoB-48-carrying remnants in apoE-deficient mice is caused by the inhibition of an as yet uncharacterized apoE-independent mechanism of removal of remnant from the circulation by the liver.

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A role for PPARα in the control of SREBP activity and lipid synthesis in the liver

Biochemical Journal ◽

10.1042/bj20041896 ◽

2005 ◽

Vol 389 (2) ◽

pp. 413-421 ◽

Cited By ~ 115

Author(s):

Brian L. Knight ◽

Abdel Hebbachi ◽

David Hauton ◽

Anna-Marie Brown ◽

David Wiggins ◽

...

Keyword(s):

Fatty Acid ◽

Cholesterol Synthesis ◽

Fatty Acid Synthase ◽

De Novo ◽

Regulatory Element ◽

Active Form ◽

Dietary Cholesterol ◽

Acid Oxidation ◽

Mrna Levels ◽

Hepatic Expression

Inclusion of the PPARα (peroxisome-proliferator-activated receptor α) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARα expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARα-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.

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CD36-dependent fatty acid uptake regulates expression of peroxisome proliferator activated receptors

Biochemical Society Transactions ◽

10.1042/bst0330311 ◽

2005 ◽

Vol 33 (1) ◽

pp. 311-315 ◽

Cited By ~ 24

Author(s):

V.A. Drover ◽

N.A. Abumrad

Keyword(s):

Plasma Lipids ◽

Fatty Acid Uptake ◽

Peroxisome Proliferator ◽

Acid Uptake ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors ◽

Induced Changes ◽

Deficient Mice

CD36 is an important regulator of lipid metabolism in vivo due to its role in the facilitated uptake of long-chain FAs (fatty acids). CD36-deficient mice display reduced TAG (triacylglycerol) in muscle, but elevated hepatic TAG. Also, insulin sensitivity is enhanced peripherally, while it appears impaired in the liver [Goudriaan, Dahlmans, Teusink, Ouwens, Febbraio, Maassen, Romijn, Havekes, and Voshol (2003) J. Lipid. Res. 44, 2270–2277; and Hajri, Han, Bonen and Abumrad (2002) J. Clin. Invest. 109, 1381–1389]. Tissues such as muscle, which normally express high levels of CD36, shift to high glucose utilization in CD36 deficiency [Hajri, Han, Bonen and Abumrad (2002) J. Clin. Invest. 109, 1381–1389], so we hypothesized that this shift must involve adaptive changes in the PPAR (peroxisome-proliferator-activated receptor) transcription factors which regulate FA metabolism. To test this, we examined mRNA levels for the three PPAR isoforms in tissues of WT (wild-type) and CD36-deficient mice following the administration of saline, glucose or olive oil by intragastric gavage. Compared with WT mice, CD36-null mice had 5–10-fold increased PPAR mRNA in adipose tissue in the basal state, and did not exhibit diet-induced changes. Correlations between adipose PPAR mRNA abundance and plasma lipids were observed in WT mice, but not in CD36-null mice. The opposite was true for hepatic PPAR mRNA levels, which correlated with plasma FA, TAG and/or glucose only in CD36-null mice. No significant differences were observed in PPAR mRNA levels in the intestine, where CD36 does not impact on FA uptake. The data suggest that CD36 and the PPARs are components of the FA-sensing machinery to respond to changes in FA flux in a tissue-specific manner.

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Hyperlipidaemic effect of fish oil in Bio F1B hamsters

British Journal Of Nutrition ◽

10.1079/bjn20031056 ◽

2004 ◽

Vol 91 (3) ◽

pp. 341-349 ◽

Cited By ~ 17

Author(s):

Pujitha P. de Silva ◽

Phillip J. Davis ◽

Sukhinder Kaur Cheema

Keyword(s):

Fish Oil ◽

Mrna Expression ◽

Plasma Lipids ◽

Control Diet ◽

Dietary Cholesterol ◽

Ldl Receptor ◽

Safflower Seed ◽

Mrna Levels ◽

Receptor Mrna ◽

Fish Oil Diet

We investigated the dietary influence of low and high levels of fish oil, supplemented with or without dietary cholesterol, on the plasma lipoprotein profile in Bio F1B hamsters, a model susceptible to diet-induced hyperlipidaemia. The MIX diet, a diet supplemented with a mixture of lard and safflower-seed oil, was used as the control diet to maintain the saturated MUFA and PUFA levels similar to the fish-oil diet. The animals were fed the specific diets for 2 weeks and fasted for 14h before killing. The plasma from the animals fed high levels of fish oil was milky and rich in chylomicron-like particles. The plasma total cholesterol, VLDL- and LDL-cholesterol and -triacylglycerol concentrations were significantly higher, whereas HDL-cholesterol was lower in hamsters fed fish oil compared with the MIX-diet-fed hamsters. Increasing the amount of fat in the diet increased plasma lipids in both the fish-oil- and the MIX-diet-fed hamsters; however, this hyperlipidaemic effect of dietary fat level was greater in the hamsters fed the fish-oil diet. The hepatic lipid concentrations were not dramatically different between the fish-oil-fed and the MIX-diet-fed hamsters. However, the hepatic LDL-receptor mRNA levels were significantly low in the fish-oil-fed hamsters compared with the MIX-diet-fed hamsters. Increasing the amount of fish oil in the diet further decreased the hepatic LDL-receptor mRNA expression. It is concluded that F1B hamsters are susceptible to fish-oil-induced hyperlipidaemia, especially at high fat levels, and this increase is partially explained by the inhibition of hepatic LDL-receptor mRNA expression.

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Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Scientific Reports ◽

10.1038/s41598-019-52253-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Amar Bahadur Singh ◽

Jingwen Liu

Keyword(s):

Mrna Expression ◽

Plasma Cholesterol ◽

Lipid Lowering ◽

High Cholesterol Diet ◽

Chow Diet ◽

Mrna Levels ◽

New Findings ◽

Deficient Mice

Abstract TRIB1 is a GWAS locus associated with plasma cholesterol and triglycerides (TG) levels. In mice, liver-specific overexpression of TRIB1 lowers plasma lipid levels. Berberine (BBR) is a natural lipid lowering drug that reduces plasma LDL-cholesterol (LDL-C), total cholesterol (TC) and TG in hyperlipidemic patients and in mice by mechanisms involving upregulation of hepatic LDL receptor (LDLR). Here, we demonstrated that BBR treatment reduced plasma LDL-C, TC and TG in LDLR wildtype (WT) mice fed a high fat and high cholesterol diet and it only lowered TG in LDLR WT mice fed a normal chow diet. In hypercholesterolemic LDLR deficient mice (Ldlr−/−), BBR treatment reduced plasma TG levels by 51% compared to the vehicle control without affecting plasma cholesterol levels. Hepatic gene expression analysis revealed that Trib1 mRNA levels were significantly elevated by BBR treatment in all three mouse models and increases of Trib1 mRNA expression were associated with reduced expression of lipogenic genes including Cebpa, Acc1 and Scd1. In vitro studies further demonstrate that BBR induces TRIB1 mRNA expression by a transcriptional mechanism via ERK signaling pathway. These new findings warrant future in vivo studies to determine the causal role of Trib1 in BBR-mediated TG lowering independent of LDLR regulation.

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Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice

Biochemical Journal ◽

10.1042/bj20020981 ◽

2003 ◽

Vol 369 (3) ◽

pp. 539-547 ◽

Cited By ~ 115

Author(s):

Tineke KOK ◽

Vincent W. BLOKS ◽

Henk WOLTERS ◽

Rick HAVINGA ◽

Peter L.M. JANSEN ◽

...

Keyword(s):

Multidrug Resistance ◽

Bile Salt ◽

Organic Anion ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Wild Type ◽

Bile Formation ◽

Peroxisome Proliferator Activated Receptor ◽

Hepatic Expression ◽

Protein Levels

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 (Mdr2), encoding the canalicular phospholipid translocator. The physiological role of PPARα in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a/1b, Abca1 and Abcg5/Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na+-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide 1 gene) or in bile formation between wild-type and Pparα(-/-) mice. Upon treatment of wild-type mice with ciprofibrate (0.05%, w/w, in diet for 2 weeks), the expression of Mdr2 (+3-fold), Mdr1a (+6-fold) and Mdr1b (+11-fold) mRNAs was clearly induced, while that of Oatp1 (-5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wild-type mouse hepatocytes to PPARα agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a/1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Pparα(-/-) mice. In conclusion, our results show that basal bile formation is not affected by PPARα deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARα, while the induction of Mdr1a/1b in vivo probably reflects a secondary phenomenon related to chronic PPARα activation.

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