Acute High-Altitude Exposure Increases Transcription of Tricarboxylic Acid Cycle Enzymes in Human Duodenal Biopsies

Abstract

Background:

A recent study of our group quantifying ¹³C-octanoate metabolism in HA (Capanna Margherita [MG]/4,559 m) showed that acute HA exposure might lead to an increase of the lipolytic and CO₂-producing pathways.

Objective:

To further test this hypothesis, we investigated intestinal biopsies from the same participants from simultaneously performed endoscopy studies for changes of mRNA-expression levels of the beta-oxidation enzymes and the decarboxylating tricarboxylic acid cycle (TCA) enzymes.

Methods:

Duodenal biopsies of 16 subjects exposed to HA were sampled via gastro-duodenoscopy at Zurich (baseline ZH, 490 m), on day 2 (MG2) and on day 4 at HA (MG4). After mRNA extraction, quantitative real-time polymerase chain reaction was performed to assess mRNAs expression of TCA cycle enzymes as well as beta-oxidation enzymes.

Results:

Aconitase mRNA levels increased early (MG2 vs. ZH, p < 0.05) and were still higher at day 4 compared with ZH (MG4 vs. ZH, p < 0.05). Isocitrate dehydrogenase (DH) levels increased with time spent at 4,559 m (MG4 vs. ZH, p < 0.01). The remaining TCA cycle and beta-oxidation enzymes investigated tended to higher values at HA but without reaching significance.

Conclusion:

We conclude that acute exposure to HA leads to increased transcription of aconitase and isocitrate DH in the duodenal mucosa due to hypobaric hypoxia exposure.

Keywords

acute mountain sickness beta-oxidation citrate acid cycle Krebs cycle lipids metabolism

Introduction

Acute high altitude (HA) exposure has crucial effects on body homeostasis and metabolism due to the deficiency of oxygen (Swenson and Bärtsch, 2014). Besides glycolysis and oxidative phosphorylation, beta-oxidation and the tricarboxylic acid cycle (TCA cycle, citric acid cycle, Krebs cycle) represent the main steps in aerobic metabolism (Nelson and Cox, 2021). It is known that hypobaric hypoxia in HA interferes with these metabolic pathways (Murray et al., 2018) (Liu et al., 2023). In a recently published study that assessed gastric emptying (GE) by the ¹³C-octanoate breath test in HA, we discovered that HA exposure must have led to profound metabolic changes in the above-mentioned pathways, such that the key assumption that underlies the performance and analysis of the GE breath test was undermined (Strunz et al., 2022): Specifically, instead of the expected delayed exhalation of ¹³CO₂ by reduced GE the complete opposite was noticed during acute HA exposure, namely increased ¹³CO₂-exhalation at HA (Strunz et al., 2022). We inferred that metabolic adaptations of the lipolytic and CO₂-producing pathway in the liver and intestine must have led to this observation (Strunz et al., 2022). Due to the study design as well as ethical and safety concerns, liver biopsy was not performed at HA. However, duodenal biopsies were performed for assessing gastrointestinal inflammation as well as intestinal iron metabolism in HA in the same individuals during the study program (Goetze et al., 2013) (Wojtal et al., 2014). Due to the close embryogenic relationship of enterocytes and hepatocytes, we hypothesized that the same changes in the aerobic metabolic pathways that occur in hepatocytes may also be present in enterocytes at HA (Sadler, 2018). To test this hypothesis, we investigated the intestinal biopsies collected from the above-mentioned endoscopy studies on Capanna Margherita (Monte Rosa region, 4,559 m) for changes of mRNA-expression levels of the beta-oxidation enzymes and the decarboxylating TCA cycle enzymes.

Materials and Methods

Study design

This post-hoc analysis was part of a series of studies assessing different aspects of HA acclimatization. The present sub-study aimed to investigate metabolic adaption of duodenal enterocytes to HA; the other arms of the study have been reported separately (Strunz et al., 2022) (Goetze et al., 2013) (Wojtal et al., 2014) (Aeberli et al., 2013) (Fruehauf et al., 2020) (Siebenmann et al., 2011). The participants underwent endoscopy at Zurich 490 m (ZH) and on two following test days (d2/MG2 and d4/MG4) at the Capanna Regina Margherita HA laboratory in the Alps (4,559 m). The study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the Canton of Zurich (EK-1677). All subjects gave written informed consent before inclusion in the study.

Subjects and exposure

The study population originally consisted of 25 healthy volunteers (15 males; 10 females) with susceptibility to HAPE (HA pulmonary edema; main inclusion criterion; confirmation of HAPE susceptibility has already been described in detail elsewhere [Siebenmann et al., 2011]. In this post-hoc analysis of stored biological material, 16 biopsy samples from these subjects (10 males, 6 females) were still available after the analytic procedures described in (Strunz et al., 2022), (Goetze et al., 2013), (Wojtal et al., 2014), (Aeberli et al., 2013), (Fruehauf et al., 2020), and (Siebenmann et al., 2011). Participants were not acclimatized to HA: Stays for more than three nights above 2,500 m 1 month before HA exposure was an exclusion criterion. Baseline blood sampling and endoscopy were performed at ZH (490 m, P(O₂) 140–150 mmHg). After ascending from Alagna Valsesia (Italy, 1,205 m) to the Gnifetti hut at 3,600 m (P(O₂) 94–103 mmHg) in the Monte Rosa region, the subjects stayed at the Gnifetti hut overnight. On the following day, they climbed to the Margherita hut (MG1, 4,559 m, P(O₂) 81–91 mmHg), where all HA experiments were performed (Strunz et al., 2022) (Goetze et al., 2013) (Wojtal et al., 2014) (Aeberli et al., 2013) (Fruehauf et al., 2020) (Siebenmann et al., 2011).

Diet

After participants fasted overnight, they received a breakfast with 30% of their individual daily energy requirement. For lunch and in the afternoon, they were given two muffins enriched with ¹³C-octanoate twice. Pasta with Bolognese sauce and Parmigiano cheese was offered to them for dinner. Biscuits were also offered ad libitum. Participants were free to choose their individual food intake at dinner. The diet has already been described in detail in Aeberli et al., 2013; Spliethoff et al, 2013, and Strunz et al., 2022.

Intestinal biopsies

At the morning of each test day, we performed blood gas analysis from the radial artery using an ABL 5 blood gas analyzer (Radiometer, Copenhagen). Following IV catheter placement, participants underwent unsedated nasal gastro-duodenoscopy and mucosal biopsies were withdrawn from duodenum part II (descending part). After removal, intestinal biopsies were immediately snap-frozen with liquid nitrogen (−195°C) and stored at −80°C until RNA extraction was performed. Quantitative real-time polymerase chain reaction was performed as previously described (Meier et al., 2018) (Meier et al., 2019) (Vuille-dit-Bille et al., 2015). The abundance of the target mRNAs was calculated relative to the reference mRNA of the housekeeping gene villin, which is commonly used as a reference gene for epithelial content in small intestinal samples (Vuille-dit-Bille et al., 2015).

Statistical analysis

Continuous values were tested for normal distribution by using the Shapiro–Wilk test or the Kolmogorow-Smirnow-test (when the sample size was too small for the Shapiro–Wilk-test). When values were normally distributed, means and standard deviations were calculated, and a one-way ANOVA with Bonferroni post-test was performed for variance analysis of the means of the different conditions (ZH, MG2, and MG4). When normal distribution could not be determined, medians with interquartile ranges were calculated, and the Kruskal–Wallis test with Dunn’s multiple comparisons test was used for variance analysis. For correlation analysis, Perason’s correlation was calculated, and results were reported as Pearson’s r with the corresponding p value. For all analyzes, the statistical software GraphPad Prism was used (version 5.01, August 7, 2007).

Results

Expression of TCA-cycle enzymes is increased in duodenal enterocytes at high altitude

Aconitase mRNA levels started to increase at MG2 and were still higher at MG4 compared with ZH (Table 1). Similarly, isocitrate dehydrogenase (DH) levels increased with time spent at 4,559 m and were higher at MG4 than at ZH (Table 1). Citrate synthetase and α-ketoglutarate DH presented no changes compared to low land level (Table 1). The expression of the ketone body-providing enzyme thiolase II was also not altered at HA (Table 1). These results indicate that hypobaric hypoxia increased transcription of these TCA cycle enzymes in duodenal mucosa. The mean mRNA expression level of aconitase correlated strong with the mean amount of ¹³CO₂ produced during the ¹³C-octanoate breath test (DOB area under the curve 0–240 minutes), as reported in our previous study (aconitase with DOB; r = 0.99, p = 0.01) (Strunz et al., 2022). The mean mRNA expression levels of isocitrate DH also demonstrated a strong correlation with the mean DOB (isocitrate DH with DOB; r = 0.99, p = 0.04) (Strunz et al, 2022).

Table 1.

Measured mRNA Levels for Duodenal TCA Cycle and Beta-Oxidation Enzymes at Different Altitudes and Timepoints

		Zurich 490 m			Capanna margherita day 21st examination day, 4,559 m			Capanna margherita day 42nd examination day, 4,559 m
Parameter	Unit	n	Median/mean	25th–75th percentile/SD	n	Median/mean	25th–75th percentile/SD	n	Median/mean	25th–75th percentile/SD
TCA cycle enzymes
CS	Rel.	13	0.327	0.172	13	0.429	0.210	15	0.349	0.173
ACO	Rel.	13	1.417	1.283–1.883	14	2.479*	2.080–2.585	15	2.539*	1.343–3.112
IC DH	Rel.	13	0.180	0.134–0.219	13	0.244	0.178–0.326	14	0.262**	0.215–0.386
aKG DH	Rel.	13	0.204	0.099	14	0.321	0.165	15	0.258	0.100
Beta-oxidation enzymes
ACS	Rel.	3	0.0005	0.0003	5	0.0012	0.0008	8	0.0008	0.0005
ECH	Rel.	12	0.123	0.063	13	0.142	0.051	15	0.124	0.068
HADH	Rel.	13	0.271	0.094	13	0.316	0.099	14	0.302	0.134
kThio	Rel.	12	0.184	0.099	14	0.257	0.136	13	0.216	0.113
Ketone body degrading enzymes
Thio	Rel.	13	0.055	0.018–0.088	14	0.051	0.037–0.067	15	0.046	0.028–0.080

Data are given as median or mean and 25th/75th percentile/SD. Significant differences versus ZH are indicated by p values (* for p < 0.05, ** for p < 0.01). ACO, aconitase; ACS, acyl-CoA synthetase; aKG DH, α-ketoglutarate DH; CS, citrate synthetase; ECH, enoyl-CoA hydratase; IC DH, isocitrate DH; HADH, hydroxyl acyl DH; kThio, keto thiolase (thiolase I); Thio, thiolase II.

Beta-oxidation at high altitude is not changed in enterocytes

Acyl-CoA DH, enoyl-CoA hydratase, hydroxyl acyl DH, and keto thiolase (thiolase I) mRNA levels showed no changes at HA (Table 1). So, HA exposure did not lead to changes in transcription of these enzymes involved in beta-oxidation in enterocytes.

Discussion

In this study, we demonstrate that acute hypobaric hypoxia at 4,559 m leads to increased duodenal mRNA transcription of aconitase and isocitrate DH in mucosa biopsies obtained during unsedated endoscopy. Several other enzymes of the TCA cycle and beta-oxidation also tended to higher values at HA compared with baseline at ZH, without reaching significance.

The biological significance of increased aconitase and isocitrate DH expression is that both enzymes are crucial components of the TCA cycle, which is central to aerobic energy metabolism (Nelson and Cox, 2021). Their upregulation likely reflects a compensatory response to intracellular adenosine triphosphate (ATP) depletion caused by acute hypobaric hypoxia exposure at HA. This suggests that enterocytes are trying to maximize energy yield from available substrates despite limited oxygen availability (Nelson and Cox, 2021). We have demonstrated that ¹³C-octanoate metabolism is increased in our previous study, implying enhanced fatty acid oxidation (FAO) and subsequent TCA activity (Strunz et al, 2022). Increased TCA enzyme expression may be a downstream effect of increased FAO, whereby enterocytes might actively metabolize fatty acids to maintain an energy balance (Nelson and Cox, 2021). The implications for gastrointestinal function are that enterocytes are high-energy-demand cells (e.g., for nutrient absorption and ion transport) (Goetze et al, 2013). Enhancing TCA function could support and maintain these roles under acute hypoxic stress until further adaptive mechanisms take effect.

In the liver of rats exposed to a comparable HA of 4,300 m, increased mRNA as well as protein levels of isocitrate DH were also reported in the acute phase of HA exposure, returning to baseline levels over time due to further adaptive processes (Ni et al., 2015). These increased transcriptional and translational rates of isocitrate DH correlated with the significant intracellular decrease of ATP in hepatocytes (Ni et al., 2015). Those authors concluded that decreased hepatic ATP levels induced isocitrate DH transcription and translation in order to restore cellular ATP levels (Ni et al., 2015). Aconitase and other enzymes of the TCA cycle were not studied in this trial (Ni et al., 2015). The same study group had reported in a similar study setting that acute HA exposure also induced an increase of mRNA levels as well as protein levels of peroxisome proliferator–activated receptor (PPAR) alpha and carnitine palmitoyl transferase-I in rat liver and, thereby, an activation of the beta-oxidation as a reaction to acute HA exposure (Ni et al., 2014). PPAR alpha is known as a potent promoter of lipolytic and catalytic processes in the liver and can inhibit hypoxia inducible factor (HIF)-1 (Zhou et al., 2012) (Grabacka et al., 2022) (Lefebvre et al., 2006). Conversely, PPAR alpha itself is inhibited by HIF-1 and HIF-2 (Narravula and Colgan, 2001) (Li et al., 2017). HIF-1 as well as HIF-2 are well known for their crucial role as ubiquitous mediators of hypoxic stress (Taylor and Scholz, 2022). The accompanying studies suggested that HIFs, especially HIF-2α, significantly increase only on day 4 [(Goetze et al., 2013) Figure 4B; (Fruehauf et al., 2020) Figure 3]. These results suggest, as shown before (Li et al., 2017), that the regulative effects of HIF-2α might be delayed compared to the PPAR alpha and ATP induced effects and, thus, different metabolic patterns can be observed depending on the time exposed to hypobaric hypoxia. Based on the above observations, we infer that temporary upregulation of the TCA cycle and beta-oxidation caused by acute HA exposure might be a consequence of ATP decrease and activation of PPAR alpha, while in chronic HA adaption, increased HIF expression and activation inhibits PPAR alpha and starts to downregulate TCA and beta-oxidation levels again (Ni et al., 2015).

Regarding the TCA cycle and beta-oxidation, the above-presented results are not wholly consistent with previously published data on HA metabolism (Dutta et al., 2009) (Kennedy et al., 2001) (Chen et al., 2007). These differences might be explained by important differences in study settings: in some trials, the experiments were carried out with significantly higher HA exposure (6,000 m or even 7,000 m) with even lower oxygen partial pressures or with longer exposure times (Dutta et al., 2009) (Kennedy et al., 2001) (Chen et al., 2007). Furthermore, some investigators used hypobaric chambers or chemically induced hypoxia, conditions that might not be entirely comparable to the stress at real hypobaric hypoxia in vivo at HA (Dutta et al., 2009) (Kennedy et al., 2001) (Chen et al., 2007). Of course, more severe hypoxic conditions at higher altitudes than 4,559 m (P(O₂) 81–91 mmHg) might profoundly inhibit aerobic metabolism and stimulate different adaptive mechanisms. In our opinion, the absolute altitude should therefore be taken in account when interpreting metabolic findings in acute HA exposure studies.

Taken together, it appears that duodenal enterocytes in humans react to acute hypobaric hypoxia with upregulation of the TCA cycle as has previously been shown for hepatocytes in animal models (Liu et al., 2023) (Ni et al., 2015) (Ni et al., 2014).

Limitations

These data should be interpreted with caution due to the following limitations: i.

First, the study program was not primarily designed to investigate TCA cycle or beta-oxidation enzyme mRNA levels in duodenal biopsy samples as a primary endpoint. Thus, sample size calculation was not adapted to answer that question, and, therefore, the study might be underpowered.

ii.

Second, the analyses were performed post-hoc to explore the reasons for the unexpected results of the ¹³C-octanoate breath test obtained at HA (Strunz et al., 2022). Therefore, not all samples or enough material for the analyses were still available from each subject at the time of analysis, leading to missing values that were not imputed.

iii.

Due to the primary aim of studying acute mountain sickness, mainly HAPE-susceptible individuals were enrolled into the study. This predisposition to HA-caused disorders might be partly mediated by more hypoxia-prone pathways. Therefore, transfer of the results to the general population should be performed with caution (selection bias).

iv.

One further limitation of our study is the cellular heterogeneity of duodenal biopsies, which may include non-epithelial cells such as immune infiltrates, particularly under inflammatory conditions. However, given that enterocytes constitute the predominant cell type in the duodenal mucosa, we expect that the majority of the measured gene expression originates from these cells.

Notwithstanding the above, these findings are novel and important because comparable data on human liver metabolism at HA in vivo is lacking. Furthermore, to our knowledge, this is the first time that the effects of hypobaric hypoxia on aerobic metabolism in duodenal or small intestinal enterocytes have been performed.

Conclusion

Together with our previously reported data (Strunz et al., 2022) and the results of mice and rat models of hypobaric hypoxia exposure (Liu et al., 2023) (Ni et al., 2015) (Ni et al., 2014), the results of the present study indicate that acute exposure to HA increases TCA cycle and beta-oxidative capacities in human duodenal mucosa by overexpression of several enzymes. These processes might be the consequence of intracellular depletion of ATP and activation of PPAR alpha. Chronic exposition to hypobaric hypoxia might reverse these processes by a better metabolic adaption caused by progressive hypoxia-induced HIF-expression.

Authors’ Contributions

M.F., M.M., M.G., H.F., T.A.L., and O.G. conceived and designed research, R.N.V.-d.-B. performed experiments, P.P.S., R.N.V.-d.-B., and O.G. analyzed data, all authors interpreted results of experiments, P.P.S. and O.G. prepared figures. All authors drafted the article, edited and revised the article. All authors approved final version of article.

Footnotes

Acknowledgments

This study is part of a cooperative project (principal investigators: M. Maggiorini & Th. Lutz) supported by the Zurich Centre for Integrative Human Physiology (ZIHP).

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Data Availability

Data can be requested from the authors by reasonable request.

Grants

This study was supported by the Zurich Center for Integrative Human Physiology, Swiss National Science Foundation, Switzerland (grant P2ZHP3_168561) (T.G.), and a Novartis Foundation for Medical-Biological Research, Switzerland grant (T.G.).

References

Aeberli

, Erb

, Spliethoff

, et al. Disturbed eating at high altitude: Influence of food preferences, acute mountain sickness and satiation hormones. Eur J Nutr, 2013; 52(2):625–635; doi: 10.1007/s00394-012-0366-9

Chen

, Wang

, Du

, et al. Diversities in hepatic HIF-1, IGF-I/IGFBP-1, LDH/ICD, and their mRNA expressions induced by CoCl(2) in Qinghai-Tibetan plateau mammals and sea level mice. Am J Physiol Regul Integr Comp Physiol, 2007; 292(1):R516–R26; doi: 10.1152/ajpregu.00397.2006

Dutta

, Vats

, Singh

, et al. Impairment of mitochondrial beta-oxidation in rats under cold-hypoxic environment. Int J Biometeorol, 2009; 53(5):397–407; doi: 10.1007/s00484-009-0224-5

Fruehauf

, Vavricka

, Lutz

, et al. Evaluation of Acute Mountain Sickness by Unsedated Transnasal Esophagogastroduodenoscopy at High Altitude. Clin Gastroenterol Hepatol, 2020; 18(10):2218–2225; doi: 10.1016/j.cgh.2019.11.036

Goetze

, Schmitt

, Spliethoff

, et al. Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers. Hepatology, 2013; 58(6):2153–2162; doi: 10.1002/hep.26581

Grabacka

, Płonka

, Pierzchalska

. The PPARα Regulation of the Gut Physiology in Regard to Interaction with Microbiota, Intestinal Immunity, Metabolism, and Permeability. Int J Mol Sci, 2022; 23(22):14156; doi: 10.3390/ijms232214156

Kennedy

, Stanley

, Panchal

, et al. Alterations in enzymes involved in fat metabolism after acute and chronic altitude exposure. J Appl Physiol (1985), 2001; 90(1):17–22; doi: 10.1152/jappl.2001.90.1.17

Lefebvre

, Chinetti

, Fruchart

, et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest, 2006; 116(3):571–580; doi: 10.1172/JCI27989

, Du

, Yuan

, et al. Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity. Free Radic Biol Med, 2017; 110:102–116; doi: 10.1016/j.freeradbiomed.2017.06.002

10.

Liu

, Li

, Liao

, et al. Energy metabolic mechanisms for high altitude sickness: Downregulation of glycolysis and upregulation of the lactic acid/amino acid-pyruvate-TCA pathways and fatty acid oxidation. Sci Total Environ, 2023; 894:164998; doi: 10.1016/j.scitotenv.2023.164998

11.

Meier

, Camargo

, Hunziker

, et al. Intestinal IMINO transporter SIT1 is not expressed in human newborns. Am J Physiol Gastrointest Liver Physiol, 2018; 315(5):G887–G895; doi: 10.1152/ajpgi.00318.2017

12.

Meier

, Camargo

SMR

, Hunziker

, et al. Mucosal Monosaccharide Transporter Expression in Newborns With Jejunoileal Atresia and Along the Adult Intestine. J Pediatr Gastroenterol Nutr, 2019; 69(5):611–618; doi: 10.1097/MPG.0000000000002425

13.

Murray

, Montgomery

, Feelisch

, et al. Metabolic adjustment to high-altitude hypoxia: From genetic signals to physiological implications. Biochem Soc Trans, 2018; 46(3):599–607; doi: 10.1042/BST20170502

14.

Narravula

, Colgan

. Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol, 2001; 166(12):7543–7548; doi: 10.4049/jimmunol.166.12.7543

15.

Nelson

, Cox

. Lehninger Principles of Biochemistry. W. H. Freeman/Macmillan Learning: New York; 2021.

16.

, Shao

, Wang

, et al. Impact of high altitude on the hepatic fatty acid oxidation and synthesis in rats. Biochem Biophys Res Commun, 2014; 446(2):574–579; doi: 10.1016/j.bbrc.2014.03.001

17.

, Wan

, Jing

, et al. Effect of Acute and Chronic Exposure to High Altitude on the Aerobic and Anaerobic Metabolism in Rats. Anal Cell Pathol (Amst), 2015; 2015:159549; doi: 10.1155/2015/159549

18.

Sadler

. Chapter 15: Development of the Digestive System. ( Sadler

. ed) In: Langman’s Medical Embryology (14th ed). s.l.: Wolters Kluwer: Philadelphia; 2018.

19.

Siebenmann

, Bloch

, Lundby

, et al. Dexamethasone improves maximal exercise capacity of individuals susceptible to high altitude pulmonary edema at 4559 m. High Alt Med Biol, 2011; 12(2):169–177; doi: 10.1089/ham.2010.1075

20.

Spliethoff

, Meier

, Aeberli

, et al. Reduced insulin sensitivity as a marker for acute mountain sickness? High Alt Med Biol, 2013; 14(3):240–250; doi: 10.1089/ham.2012.1128

21.

Strunz

, Vuille-Dit-Bille

, R Fox

, et al. Effect of high altitude on human postprandial 13 C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception. Neurogastroenterol Motil, 2022; 34(3):e14225; doi: 10.1111/nmo.14225

22.

Swenson

, Bärtsch

.(eds). High Altitude: Human Adaptation to Hypoxia. Springer Science+Business Media: New York; 2014.

23.

Taylor

, Scholz

. The effect of HIF on metabolism and immunity. Nat Rev Nephrol, 2022 Sep;18(9):573–587; doi: 10.1038/s41581-022-00587-8

24.

Vuille-dit-Bille

, Camargo

, Emmenegger

, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids, 2015; 47(4):693–705; doi: 10.1007/s00726-014-1889-6

25.

Wojtal

, Cee

, Lang

, et al. Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans. Am J Physiol Gastrointest Liver Physiol, 2014; 307(7):G673–G88; doi: 10.1152/ajpgi.00353.2013

26.

Zhou

, Zhang

, Xue

, et al. Activation of peroxisome proliferator-activated receptor α (PPARα) suppresses hypoxia-inducible factor-1α (HIF-1α) signaling in cancer cells. J Biol Chem, 2012; 287(42):35161–35169; doi: 10.1074/jbc.M112.367367