scholarly journals Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism

2015 ◽  
Vol 26 (12) ◽  
pp. 2298-2310 ◽  
Author(s):  
Terhi O. Helenius ◽  
Julia O. Misiorek ◽  
Joel H. Nyström ◽  
Lina E. Fortelius ◽  
Aida Habtezion ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Mechanical Stability ◽  
Short Chain Fatty Acids ◽  
Monocarboxylate Transporter ◽  
Simple Type ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Intermediate Filament Proteins ◽  
Monocarboxylate Transporter 1 ◽  
Keratin 8

Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8−/−) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator–activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions—starvation or ketogenic diet—increase K8+/+ HMGCS2, whereas this response is blunted in the K8−/− colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8−/−. In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8−/− colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.

Monocarboxylate transporters 1 and 4: expression and regulation by PPARα in ovine ruminal epithelial cells

2014 ◽  
Vol 307 (12) ◽  
pp. R1428-R1437 ◽  
Author(s):  
Franziska Benesch ◽  
Franziska Dengler ◽  
Franziska Masur ◽  
Helga Pfannkuche ◽  
Gotthold Gäbel
Keyword(s):  
Epithelial Cells ◽  
Intracellular Ph ◽  
Target Genes ◽  
Specific Inhibitor ◽  
Short Chain Fatty Acids ◽  
Monocarboxylate Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Selective Ligand

In the intact rumen epithelium, isoforms 1 and 4 of the monocarboxylate transporter (MCT1 and MCT4) are thought to play key roles in mediating transcellular and intracellular permeation of short-chain fatty acids and their metabolites and in maintaining intracellular pH. We examined whether both MCT1 and MCT4 are expressed at mRNA and protein levels in ovine ruminal epithelial cells (REC) maintained in primary culture and whether they are regulated by peroxisome proliferator-activated receptor-α (PPARα). Because both transporters have been characterized to function coupled to protons, the influence of PPARα on the recovery of intracellular pH after l-lactate exposure was evaluated by spectrofluorometry. MCT1 and MCT4 were detected using immunocytochemistry both at the cell margins and intracellularly in cultured REC. To test regulation by PPARα, cells were exposed to WY 14.643, a selective ligand of PPARα, for 48 h. The subsequent qPCR analysis resulted in a dose-dependent upregulation of MCT1 and PPARα target genes, whereas response of MCT4 was not uniform. Protein expression of MCT1 and MCT4 quantified by Western blot analysis was not altered by WY 14.643 treatment. l-Lactate-dependent proton export was blocked almost completely by pHMB, a specific inhibitor of MCT1 and MCT4. However, l-lactate-dependent, pHMB-inhibited proton export in WY 14.643-treated cells was not significantly altered compared with cells not treated with WY 14.643. These data suggest that PPARα is particularly regulating MCT1 but not MCT4 expression. Extent of lactate-coupled proton export indicates that MCT1 is already working on a high level even under unstimulated conditions.

scholarly journals High-intensity intermittent exercise training with chlorella intake accelerates exercise performance and muscle glycolytic and oxidative capacity in rats

2017 ◽  
Vol 312 (4) ◽  
pp. R520-R528 ◽  
Author(s):  
Naoki Horii ◽  
Natsuki Hasegawa ◽  
Shumpei Fujie ◽  
Masataka Uchida ◽  
Eri Miyamoto-Mikami ◽  
...  
Keyword(s):  
Exercise Performance ◽  
Oxidative Metabolism ◽  
High Intensity ◽  
Citrate Synthase ◽  
Intermittent Exercise ◽  
Oxidative Capacity ◽  
Monocarboxylate Transporter ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor

The purpose of this study was to investigate the effect of chronic chlorella intake alone or in combination with high-intensity intermittent exercise (HIIE) training on exercise performance and muscle glycolytic and oxidative metabolism in rats. Forty male Sprague-Dawley rats were randomly assigned to the four groups: sedentary control, chlorella intake (0.5% chlorella powder in normal feed), HIIE training, and combination of HIIE training and chlorella intake for 6 wk ( n = 10 each group). HIIE training comprised 14 repeats of a 20-s swimming session with a 10-s pause between sessions, while bearing a weight equivalent to 16% of body weight, 4 days/week. Exercise performance was tested after the interventions by measuring the maximal number of HIIE sessions that could be completed. Chlorella intake and HIIE training significantly increased the maximal number of HIIE sessions and enhanced the expression of monocarboxylate transporter (MCT)1, MCT4, and peroxisome proliferator-activated receptor γ coactivator-1α concomitantly with the activities of lactate dehydrogenase (LDH), phosphofructokinase, citrate synthase (CS), and cytochrome- c oxidase (COX) in the red region of the gastrocnemius muscle. Furthermore, the combination further augmented the increased exercise performance and the enhanced expressions and activities. By contrast, in the white region of the muscle, MCT1 expression and LDH, CS, and COX activities did not change. These results showed that compared with only chlorella intake and only HIIE training, chlorella intake combined with HIIE training has a more pronounced effect on exercise performance and muscle glycolytic and oxidative metabolism, in particular, lactate metabolism.

scholarly journals Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Catherine D. Shelton ◽  
Mariana X. Byndloss
Keyword(s):  
Microbial Community ◽  
Short Chain Fatty Acids ◽  
Noncommunicable Diseases ◽  
Peroxisome Proliferator ◽  
Pathogenic Potential ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Diet Induced Obesity ◽  
Intestinal Dysbiosis ◽  
Epithelial Dysfunction

ABSTRACT In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as Proteobacteria. This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic Enterobacteriaceae, regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of Enterobacteriaceae can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.

Transport of ketone bodies and lactate in the sheep ruminal epithelium by monocarboxylate transporter 1

2002 ◽  
Vol 283 (5) ◽  
pp. G1139-G1146 ◽  
Author(s):  
Frank Müller ◽  
Korinna Huber ◽  
Helga Pfannkuche ◽  
Jörg R. Aschenbach ◽  
Gerhard Breves ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cultured Cells ◽  
Ketone Bodies ◽  
Short Chain Fatty Acids ◽  
Monocarboxylate Transporter ◽  
Monocarboxylate Transporter 1 ◽  
Protein Levels ◽  
Ruminal Epithelium ◽  
Intracellular Metabolism ◽  
Acid Extrusion

Due to intensive intracellular metabolism of short-chain fatty acids, ruminal epithelial cells generate large amounts of d-β-hydroxybutyric acid, acetoacetic acid, and lactic acid. These acids have to be extruded from the cytosol to avoid disturbances of intracellular pH (pHi). To evaluate acid extrusion, pHi was studied in cultured ruminal epithelial cells of sheep using the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Extracellular addition of d-β-hydroxybutyrate, acetoacetate, or lactate (20 mM) resulted in intracellular acidification. Vice versa, removing extracellulard-β-hydroxybutyrate, acetoacetate, or lactate after preincubation with the respective monocarboxylate induced an increase of pHi. Initial rate of pHi decrease as well as of pHi recovery was strongly inhibited by pCMBS (400 μM) and phloretin (20 μM). Both cultured cells and intact ruminal epithelium were tested for the possible presence of proton-linked monocarboxylate transporter (MCT) on both the mRNA and protein levels. With the use of RT-PCR, mRNA encoding for MCT1 isoform was demonstrated in cultured ruminal epithelial cells and the ruminal epithelium. Immunostaining with MCT1 antibodies intensively labeled cultured ruminal epithelial cells and cells located in the stratum basale of the ruminal epithelium. In conclusion, our data indicate that MCT1 is expressed in the stratum basale of the ruminal epithelium and may function as a main mechanism for removing ketone bodies and lactate together with H+ from the cytosol into the blood.

scholarly journals Proteomic Analysis Reveals the Protective Effects of Yiqi Fumai Lyophilized Injection on Chronic Heart Failure by Improving Myocardial Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoying Han ◽  
Yi Zhang ◽  
Ou Qiao ◽  
Haixia Ji ◽  
Xinyu Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Chronic Heart Failure ◽  
Heart Tissue ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Downstream Effectors

Yiqi Fumai lyophilized injection (YQFM) is the recombination of Sheng mai san (SMS).YQFM has been applied clinically to efficaciously and safely treat chronic heart failure (CHF). However, the mechanism of YQFM is still not fully elucidated. The purpose of our study was to investigate the protective mechanism of YQFM against abdominal aortic coarctation (AAC) in rats by proteomic methods. After YQFM treatment, the cardiac function were obviously meliorated. One hundred and fifty-seven important differentially expressed proteins (DEPs) were identified, including 109 in model rat compared with that in control rat (M:C) and 48 in YQFM-treated rat compared with that in model rat (T:M) by iTRAQ technology to analyze the proteomic characteristics of heart tissue. Bioinformatics analysis showed that DEPs was mainly involved in the body’s energy metabolism and was closely related to oxidative phosphorylation. YQFM had also displayed efficient mitochondrial dysfunction alleviation properties in hydrogen peroxide (H2O2)-induced cardiomyocyte damage by Transmission Electron Microscope (TEM), Metabolic assay, and Mitotracker staining. What’s more, the levels of total cardiomyocyte apoptosis were markedly reduced following YQFM treatment. Furthermore, Western blot analysis showed that the expressions of peroxisome proliferator activated receptor co-activator-1α(PGC-1α) (p < 0.01 or p < 0.001), perixisome proliferation-activated receptor alpha (PPAR-α) (p < 0.001)and retinoid X receptor alpha (RXR-α) were upregulated (p < 0.001), PGC-1α as well as its downstream effectors were also found to be upregulated in cardiomyocytes after YQFM treatment(p < 0.001).These results provided evidence that YQFM could enhance mitochondrial function of cardiomyocytes to play a role in the treatment of CHF by regulating mitochondrial biogenesis-related proteins.

scholarly journals Simulated Microgravity Suppresses Osteogenic Differentiation of Mesenchymal Stem Cells by Inhibiting Oxidative Phosphorylation

2020 ◽  
Vol 21 (24) ◽  
pp. 9747
Author(s):  
Lin Liu ◽  
Yansiwei Cheng ◽  
Jie Wang ◽  
Zhongjie Ding ◽  
Alexander Halim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Osteogenic Differentiation ◽  
Simulated Microgravity ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Mtdna Copy Number ◽  
Peroxisome Proliferator Activated Receptor

Studies showed that energy metabolism plays a pivotal role in the differentiation of stem cells. Previous studies revealed that simulated microgravity (SMG) inhibits osteogenic differentiation of mesenchymal stem cells (MSCs). However, the underlying relationship between osteogenesis and energy metabolism under SMG conditions is not fully understood. In the present study, we investigated mitochondrial oxidative phosphorylation (OXPHOS) by assessing the level of peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α), mitochondrial DNA (mtDNA) copy number, mitochondrial mass and oxygen consumption rate (OCR) during osteogenesis of MSCs under SMG conditions. We found that SMG inhibited osteogenic differentiation and OXPHOS of MSCs. Moreover, the expression of sirtuin 1 (Sirt1), an important energy sensor, significantly decreased. After upregulating the expression of Sirt1 using resveratrol, an activator of Sirt1, SMG-inhibited OXPHOS and osteogenic differentiation of MSCs were recovered. Taken together, our results suggest that SMG suppresses osteogenic differentiation of MSCs by inhibiting OXPHOS, indicating that OXPHOS might serve as a potential therapeutic target for repairing bone loss under microgravity conditions.

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