Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways

2011 ◽  
Vol 301 (5) ◽  
pp. E1022-E1032 ◽  
Author(s):  
Tsuyoshi Goto ◽  
Young-Il Kim ◽  
Kozue Funakoshi ◽  
Aki Teraminami ◽  
Taku Uemura ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Farnesoid X Receptor ◽  
Luciferase Assay ◽  
Acid Oxidation ◽  
Metabolic Abnormalities ◽  
Hepatic Triglyceride ◽  
Wild Type ◽  
Triglyceride Accumulation

Peroxisome proliferator-activated receptors (PPARs) control energy homeostasis. In this study, we showed that farnesol, a naturally occurring ligand of PPARs, could ameliorate metabolic diseases. Obese KK-Ay mice fed a high-fat diet (HFD) containing 0.5% farnesol showed significantly decreased serum glucose level, glucosuria incidence, and hepatic triglyceride contents. Farnesol-containing HFD upregulated the mRNA expressions of PPARα target genes involved in fatty acid oxidation in the liver. On the other hand, farnesol was not effective in upregulating the mRNA expressions of PPARγ target genes in white adipose tissues. Experiments using PPARα-deficient [(−/−)] mice revealed that the upregulation of fatty acid oxidation-related genes required PPARα function, but the suppression of hepatic triglyceride accumulation was partially PPARα-dependent. In hepatocytes isolated from the wild-type and PPARα (−/−) mice, farnesol suppressed triglyceride synthesis. In luciferase assay, farnesol activated both PPARα and the farnesoid X receptor (FXR) at similar concentrations. Moreover, farnesol increased the mRNA expression level of a small heterodimer partner known as one of the FXR target genes and decreased those of sterol regulatory element-binding protein-1c and fatty acid synthase in both the wild-type and PPARα (−/−) hepatocytes. These findings suggest that farnesol could improve metabolic abnormalities in mice via both PPARα-dependent and -independent pathways and that the activation of FXR by farnesol might contribute partially to the PPARα-independent hepatic triglyceride content-lowering effect. To our knowledge, this is the first study on the effect of the dual activators of PPARα and FXR on obesity-induced metabolic disorders.

scholarly journals Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia

2021 ◽  
Vol 22 (9) ◽  
pp. 4527
Author(s):  
Hana Malinská ◽  
Martina Hüttl ◽  
Denisa Miklánková ◽  
Jaroslava Trnovská ◽  
Iveta Zapletalová ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Hepatic Triglyceride ◽  
Tissue Weight ◽  
Triglyceride Accumulation ◽  
Brown Adipose

Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p ˂ 0.05) and decreased CYP4A (p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p ˂ 0.01), lipogenesis (p ˂ 0.05) and lipolysis (p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.

scholarly journals Peroxisome Proliferator-Activated Receptor α Mediates the Effects of High-Fat Diet on Hepatic Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1508-1516 ◽  
Author(s):  
David Patsouris ◽  
Janardan K. Reddy ◽  
Michael Müller ◽  
Sander Kersten
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Microarray Analysis ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Wild Type ◽  
High Fat ◽  
Fat Feeding

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPARα isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPARα. To examine whether PPARα mediates the effects of chronic high-fat feeding, wild-type and PPARα null mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 26 wk. HFD and PPARα deletion independently increased liver triglycerides. Furthermore, in wild-type mice HFD was associated with a significant increase in hepatic PPARα mRNA and plasma free fatty acids, leading to a PPARα-dependent increase in expression of PPARα marker genes CYP4A10 and CYP4A14. Microarray analysis revealed that HFD increased hepatic expression of characteristic PPARα target genes involved in fatty acid oxidation in a PPARα-dependent manner, although to a lesser extent than fasting or Wy14643. Microarray analysis also indicated functional compensation for PPARα in PPARα null mice. Remarkably, in PPARα null mice on HFD, PPARγ mRNA was 20-fold elevated compared with wild-type mice fed a LFD, reaching expression levels of PPARα in normal mice. Adenoviral overexpression of PPARγ in liver indicated that PPARγ can up-regulate genes involved in lipo/adipogenesis but also characteristic PPARα targets involved in fatty acid oxidation. It is concluded that 1) PPARα and PPARα-signaling are activated in liver by chronic high-fat feeding; and 2) PPARγ may compensate for PPARα in PPARα null mice on HFD.

scholarly journals Roles of key active-site residues in flavocytochrome P450 BM3

1999 ◽  
Vol 339 (2) ◽  
pp. 371-379 ◽  
Author(s):  
Michael A. NOBLE ◽  
Caroline S. MILES ◽  
Stephen K. CHAPMAN ◽  
Dominikus A. LYSEK ◽  
Angela C. MACKAY ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Active Site ◽  
Side Chain ◽  
Acid Oxidation ◽  
Dodecanoic Acid ◽  
Wild Type ◽  
Active Site Residues ◽  
P450 Bm3

The effects of mutation of key active-site residues (Arg-47, Tyr-51, Phe-42 and Phe-87) in Bacillus megaterium flavocytochrome P450 BM3 were investigated. Kinetic studies on the oxidation of laurate and arachidonate showed that the side chain of Arg-47 contributes more significantly to stabilization of the fatty acid carboxylate than does that of Tyr-51 (kinetic parameters for oxidation of laurate: R47A mutant, Km 859 µM, kcat 3960 min-1; Y51F mutant, Km 432 µM, kcat 6140 min-1; wild-type, Km 288 µM, kcat 5140 min-1). A slightly increased kcat for the Y51F-catalysed oxidation of laurate is probably due to decreased activation energy (ΔG‡) resulting from a smaller ΔG of substrate binding. The side chain of Phe-42 acts as a phenyl ‘cap ’ over the mouth of the substrate-binding channel. With mutant F42A, Km is massively increased and kcat is decreased for oxidation of both laurate (Km 2.08 mM, kcat 2450 min-1) and arachidonate (Km 34.9 µM, kcat 14620 min-1; compared with values of 4.7 µM and 17100 min-1 respectively for wild-type). Amino acid Phe-87 is critical for efficient catalysis. Mutants F87G and F87Y not only exhibit increased Km and decreased kcat values for fatty acid oxidation, but also undergo an irreversible conversion process from a ‘fast ’ to a ‘slow ’ rate of substrate turnover [for F87G (F87Y)-catalysed laurate oxidation: kcat ‘fast ’, 760 (1620) min-1; kcat ‘slow ’, 48.0 (44.6) min-1; kconv (rate of conversion from fast to slow form), 4.9 (23.8) min-1]. All mutants showed less than 10% uncoupling of NADPH oxidation from fatty acid oxidation. The rate of FMN-to-haem electron transfer was shown to become rate-limiting in all mutants analysed. For wild-type P450 BM3, the rate of FMN-to-haem electron transfer (8340 min-1) is twice the steady-state rate of oxidation (4100 min-1), indicating that other steps contribute to rate limitation. Active-site structures of the mutants were probed with the inhibitors 12-(imidazolyl)dodecanoic acid and 1-phenylimidazole. Mutant F87G binds 1-phenylimidazole > 10-fold more tightly than does the wild-type, whereas mutant Y51F binds the haem-co-ordinating fatty acid analogue 12-(imidazolyl)dodecanoic acid > 30-fold more tightly than wild-type.

scholarly journals Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

2004 ◽  
Vol 24 (20) ◽  
pp. 9079-9091 ◽  
Author(s):  
Janice M. Huss ◽  
Inés Pineda Torra ◽  
Bart Staels ◽  
Vincent Giguère ◽  
Daniel P. Kelly
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Cellular Fatty Acid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

Exercise, FGF21, and PGC-1 : roles in hepatic metabolism

2014 ◽  
Author(s):  
◽  
Justin Andrew Fletcher
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Gene Transcription ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Wild Type ◽  
Hepatic Fatty Acid ◽  
Exercise Induced ◽  
Hepatic Fatty Acid Oxidation ◽  
Mitochondrial Adaptations

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The liver is instrumental in maintaining euglycemia during times of fasting and exercise, and in-turn exercise is a stimulus that challenges the liver and results in hepatic mitochondrial adaptations. Mechanisms responsible for these improvements in mitochondrial function are not currently known. Fibroblast growth factor 21 (FGF21), a powerful metabolic regulator, is one potential mechanism responsible for exercise- induced hepatic mitochondrial adaptations. Previous studies show that FGF21 modulates hepatic fatty acid oxidation (FAO), gluconeogenesis, ketogenesis, and TCA cycle flux, in addition to gene transcription of proteins important to these processes. The purpose of the first objective in the current study was to examine whether FGF21 is necessary for exercise to induce hepatic mitochondrial adaptations in mice. A second objective was to determine if PGC--1? is responsible for the upregulation of genes important to metabolic processes in response to FGF21 signaling. We mechanistically assessed the necessity of FGF21 for exercise-induced hepatic mitochondrial adaptations by providing wild-type and FGF21 knockout mice with running wheels for 8 weeks to promote physical activity. A major finding in the current study is that the FGF21KO mice experience a hepatic fatty acid oxidation deficit compared to the wild-type group and that 8 weeks of voluntary wheel running normalized FAO in the FGF21KO mice. The role of PGC-1[alpha] in FGF21 regulation of gene transcription was also assessed by continuously administering FGF21 (1 mg/kg), or saline into wild-type or liver specific PGC--1[alpha] heterozygous mice (LPGC--1[alpha]) for 4 weeks. It was found that female mice did not express a phenotype effect; however, in male mice hepatic FAO was significantly blunted in the LPGC-1[alpha] mice, yet FGF21 administration was able to elevate FAO regardless in both genotypes. Collectively, this data suggests that FGF21 is necessary for the expression and content of certain genes or proteins, but that VWR is able to circumvent the absence of FGF21 and normalize hepatic FAO. Furthermore, a reduction in hepatic PGC-1[alpha] does not appear to influence the ability of FGF21 to regulate hepatic FAO.

Abstract 17085: Metabolic Signature of Human Right Ventricular Heart Muscle in Pulmonary Arterial Hypertension and Comparison to Two Animal Models

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Giovanni E Davogustto ◽  
Megha Talati ◽  
Niki Penner ◽  
Kelsey Tomasek ◽  
Yan Ru Su ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Changes ◽  
Acid Oxidation ◽  
Long Chain Fatty Acids ◽  
Wild Type ◽  
Human Right ◽  
Metabolic Signature ◽  
Pulmonary Arterial ◽  
Long Chain

Introduction: Molecular studies of the human right ventricle (RV) in pulmonary arterial hypertension (PAH) are lacking. Metabolic changes in the failing RV vary across different animal models and have not been directly compared with the human RV. We hypothesized that the BMPR2 murine model of PAH would closely recapitulate metabolic changes in the human PAH RV Methods: We performed metabolomic profiling of 596 compounds (Metabolon) on: RV specimens from patients with PAH and non-PAH controls (n=3 per group), BMPR2 mice (n=15), wild-type mice after pulmonary artery banding (PAB) (n=7), and wild-type control mice (WT) (n=7). Normalized metabolites per group were compared by Welch’s t-test between two groups, and two-way ANOVA for >2 groups, followed by adjustment for multiple comparison analysis Results: Principal component analysis (PCA) revealed markedly different metabolic profiles between PAH and controls ( Figure 1A ), with significant changes in 131 biochemicals in PAH. We observed an increase in glycolysis as evident by lactate accumulation and reduction in glycolytic intermediaries. We also observed a substantial reduction in fatty acid oxidation in the PAH RV, characterized by markedly reduced acylcarnitines and accumulation of long chain fatty acids, lysolipids, and glycerol compounds ( Figure 1B ). The BMPR2 model significantly reproduced the direction of difference in 43/131 metabolites and the PAB model 29/131. Both models were associated with an increase in glycolysis but only the BMPR2 model showed evidence of impaired fatty acid oxidation (accumulation of long-chain fatty acids, lysolipids, glycerol, and monoacylglycerols), as observed in the human PAH RV ( Figure 1C ) Conclusions: The failing RV of patients with PAH has a distinct metabolic signature characterized by increased glycolysis and impaired fatty acid oxidation. The BMPR2 model of PAH recapitulates more of the key metabolic changes observed in humans compared with a model of isolated pressure overload. The BMPR2 model may be preferable for metabolic studies of the failing RV

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