Musutova Martina, Elkalaf Moustafa, Klubickova Natalie, Koc Michal, Povysil Stanislav, Rambousek Jan, Volckaert Beatriz, Duska Frantisek, Trinh Minh Duc, Kalous Martin, Trnka Jan, Balusikova Kamila, Kovar Jan, Polak Jan
Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia.
Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czechia.
Front Endocrinol (Lausanne). 2018 Oct 17;9:616. doi: 10.3389/fendo.2018.00616. eCollection 2018.
Metabolic impairments associated with obstructive sleep apnea syndrome (OSA) are linked to tissue hypoxia, however, the explanatory molecular and endocrine mechanisms remain unknown. Using gas-permeable cultureware, we studied the chronic effects of mild and severe hypoxia on free fatty acid (FFA) uptake, storage, and oxidation in L6 myotubes under 20, 4, or 1% O. Additionally, the impact of metformin and the peroxisome proliferator-activated receptor (PPAR) β/δ agonist, called GW501516, were investigated. Exposure to mild and severe hypoxia reduced FFA uptake by 37 and 32%, respectively, while metformin treatment increased FFA uptake by 39% under mild hypoxia. GW501516 reduced FFA uptake under all conditions. Protein expressions of CD36 (cluster of differentiation 36) and SCL27A4 (solute carrier family 27 fatty acid transporter, member 4) were reduced by 17 and 23% under severe hypoxia. Gene expression of UCP2 (uncoupling protein 2) was reduced by severe hypoxia by 81%. Metformin increased CD36 protein levels by 28% under control conditions and SCL27A4 levels by 56% under mild hypoxia. Intracellular lipids were reduced by mild hypoxia by 18%, while in controls only, metformin administration further reduced intracellular lipids (20% O) by 36%. Finally, palmitate oxidation was reduced by severe hypoxia, while metformin treatment reduced non-mitochondrial O consumption, palmitate oxidation, and proton leak at all O levels. Hypoxia directly reduced FFA uptake and intracellular lipids uptake in myotubes, at least partially, due to the reduction in CD36 transporters. Metformin, but not GW501516, can increase FFA uptake and SCL27A4 expression under mild hypoxia. Described effects might contribute to elevated plasma FFA levels and metabolic derangements in OSA.
与阻塞性睡眠呼吸暂停综合征（OSA）相关的代谢障碍与组织缺氧有关，然而，其解释性的分子和内分泌机制仍不清楚。我们使用透气培养器皿，研究了轻度和重度缺氧对L6肌管在20%、4%或1%氧气条件下游离脂肪酸（FFA）摄取、储存和氧化的慢性影响。此外，还研究了二甲双胍和过氧化物酶体增殖物激活受体（PPAR）β/δ激动剂GW501516的影响。暴露于轻度和重度缺氧分别使FFA摄取减少37%和32%，而在轻度缺氧条件下，二甲双胍治疗使FFA摄取增加39%。GW501516在所有条件下均降低FFA摄取。在重度缺氧条件下，CD36（分化簇36）和SCL27A4（溶质载体家族27脂肪酸转运蛋白成员4）的蛋白表达分别降低17%和23%。UCP2（解偶联蛋白2）的基因表达在重度缺氧条件下降低81%。在对照条件下，二甲双胍使CD36蛋白水平增加28%，在轻度缺氧条件下使SCL27A4水平增加56%。轻度缺氧使细胞内脂质减少18%，而仅在对照组中，给予二甲双胍进一步使细胞内脂质（20%氧气）减少36%。最后，重度缺氧降低了棕榈酸氧化，而二甲双胍治疗在所有氧气水平下均降低了非线粒体氧气消耗、棕榈酸氧化和质子泄漏。缺氧直接降低了肌管中FFA摄取和细胞内脂质摄取，至少部分是由于CD36转运蛋白的减少。在轻度缺氧条件下，二甲双胍而非GW501516可增加FFA摄取和SCL27A4表达。所述效应可能导致OSA患者血浆FFA水平升高和代谢紊乱。
