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.
AeberliI, ErbA, SpliethoffK, 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
2.
ChenXQ, WangSJ, DuJZ, 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
3.
DuttaA, VatsP, SinghVK, 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
4.
FruehaufH, VavrickaSR, LutzTA, 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
5.
GoetzeO, SchmittJ, SpliethoffK, 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
6.
GrabackaM, PłonkaPM, PierzchalskaM. 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
7.
KennedySL, StanleyWC, PanchalAR, 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
8.
LefebvreP, ChinettiG, FruchartJC, 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
9.
LiD, DuY, YuanX, 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.
LiuG, LiY, LiaoN, 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.
MeierC, CamargoSM, HunzikerS, 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.
MeierCF, CamargoSMR, HunzikerS, 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.
MurrayAJ, MontgomeryHE, FeelischM, 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.
NarravulaS, ColganSP. 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.
NelsonDL, CoxMM. Lehninger Principles of Biochemistry. W. H. Freeman/Macmillan Learning: New York; 2021.
16.
NiQ, ShaoY, WangYZ, 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.
NiQ, WanFQ, JingYH, 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.
SadlerTW. Chapter 15: Development of the Digestive System. (SadlerTW. ed) In: Langman’s Medical Embryology (14th ed). s.l.: Wolters Kluwer: Philadelphia; 2018.
19.
SiebenmannC, BlochKE, LundbyC, 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.
SpliethoffK, MeierD, AeberliI, 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.
StrunzPP, Vuille-Dit-BilleRN, R FoxM, 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.
SwensonER, BärtschP.(eds). High Altitude: Human Adaptation to Hypoxia. Springer Science+Business Media: New York; 2014.
23.
TaylorCT, ScholzCC. 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-BilleRN, CamargoSM, EmmeneggerL, 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.
WojtalKA, CeeA, LangS, 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.
ZhouJ, ZhangS, XueJ, 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
