Chronic hypoxia reduces cold tolerance <italic style="font-style: italic">via</italic> hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression

HUANG Yujie; HUANG Lingfang; ZHEGN Minghai; XIONG Kun; TAN Xiaoling

doi:10.16016/j.2097-0927.202510098

您当前的位置：

首页 >

文章列表页 >

Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression

Basic Medicine | 更新时间：2026-01-14

- Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression
- Journal of Army Medical University Vol. 48, Issue 1, Pages: 54-62(2026)
- 作者机构：
  
  1.陆军军医大学（第三军医大学）：高原军事医学系寒区医学教研室，极端环境医学教育部重点实验室
  2.陆军军医大学（第三军医大学）：高原军事医学系寒区医学教研室，护理系临床护理学教研室
  3.Department of Clinical Nursing, School of Nursing， Army Medical University （Third Military Medical University）， Chongqing， China
- 作者简介：
  
  TAN Xiaoling E-mail：tanxl0511@163.com
- 基金信息：
  
  Supported by the General Program of National Natural Science Foundation of China(32071122)
- DOI：10.16016/j.2097-0927.202510098
  CLC： R339.55;R341;R364.4
- Received：10 October 2025，
  
  Revised：2025-12-02，
  
  Accepted：16 December 2025，
  
  Published：15 January 2026
- 稿件说明：
移动端阅览
黄榆杰，黄玲芳，郑明海，等.慢性低氧通过肝因子ANGPTL3介导的线粒体损伤与脂肪产热抑制降低耐寒能力［J］.陆军军医大学学报，2026，48（01）：54-62.DOI：10.16016/j.2097-0927.202510098.

HUANG Y J，HUANG L F，ZHEGN M H，et al.Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression［J］.J Army Med Univ，2026，48（01）：54-62.DOI：10.16016/j.2097-0927.202510098.
黄榆杰，黄玲芳，郑明海，等.慢性低氧通过肝因子ANGPTL3介导的线粒体损伤与脂肪产热抑制降低耐寒能力［J］.陆军军医大学学报，2026，48（01）：54-62.DOI：10.16016/j.2097-0927.202510098. DOI：

HUANG Y J，HUANG L F，ZHEGN M H，et al.Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression［J］.J Army Med Univ，2026，48（01）：54-62.DOI：10.16016/j.2097-0927.202510098. DOI：

摘要

目的

探讨肝因子血管生成素样蛋白3（angiopoietin-like 3，ANGPTL3）在慢性低氧暴露导致耐寒能力下降中的作用及机制。

方法

①7~8周龄、体质量220~260 g的雄性SD大鼠随机分为（

=20）：常氧组［N组，海拔308 m、（24.0±0.5）℃常氧环境饲养］和低氧组［H组，模拟海拔5 800 m、（24.0±0.5）℃低压氧舱饲养］，每组选取12只大鼠在腹腔埋入可测体温的植入子用于后续测核心体温（core body temperature

Tc）。②雄性SD大鼠随机分为（

=20）：低氧（H）组和低氧+ANGPTL3抑制剂（每周Vupanorsen 2 mg/kg腹腔注射1次）干预（H+V）组，每组选取12只大鼠在腹腔埋入可测体温的植入子用于后续测Tc，大鼠均于模拟海拔5 800 m、（24.0±0.5）℃低压氧舱饲养。6周后，每组取未埋入植入子的8只大鼠采集血液及肝组织，自动生化分析仪测定血清谷草转氨酶（aspartate aminotransferase

AST）水平，ELISA法检测血液肝因子水平，透射电镜观察肝细胞线粒体形态，Western blot检测肝组织ANGPTL3蛋白水平。每组埋入植入子的12只大鼠分别置于低氧寒冷环境（模拟海拔5 800 m、6 ℃）下24 h或置于常氧寒冷环境（海拔308 m、-10 ℃）下6 h，用生理信号遥测系统检测Tc以评价耐寒能力，Western blot检测皮下白色脂肪组织的解偶联蛋白1（uncoupling protein 1，UCP1）蛋白水平以评估白色脂肪棕色化程度。

结果

①与低氧常温环境（5 800 m、24 ℃）暴露相比，H组大鼠在低氧寒冷环境（5 800 m、6 ℃）暴露后的Tc显著降低（

0.05）。②常氧寒冷环境下（308 m、-10 ℃、6 h），N组和H组大鼠Tc均显著下降，且H组Tc显著低于N组（

0.05）。③与N组相比，H组大鼠血清ANGPTL3水平显著增加（

=7.3，

=10，95%

：2.553~2.687，

0.000 1），肝脏ANGPTL3蛋白水平也显著增加（

=6.532，

=10，95%

：26.98~54.92，

0.000 1）。④与H组相比，H+V组大鼠血清ANGPTL3水平显著降低（

=7.803，

=10，95%

：-196.8~-109.4，

=0.000 4），肝脏ANGPTL3蛋白水平也显著降低（

=3.514，

=10，95%

：-66.14~-14.81，

=0.006）。⑤在常氧寒冷环境暴露（308 m、-10 ℃、6 h），H组和H+V组大鼠Tc均显著下降，且H+V组Tc显著高于H组（95%

：-0.629~-0.452，

=0.000 4）。⑥在低氧寒冷环境暴露（5 800 m、6 ℃、24 h），H组和H+V组大鼠Tc均显著下降，且H+V组Tc显著高于H组（95%

：-0.568~-4.431，

=0.018 1）。⑦与N组相比，H组大鼠肝细胞线粒体形态结构明显损伤、血清AST水平显著升高（

=14.15，

=14，95%

：51.61~70.04，

0.000 1）。⑧与H组相比，H+V组大鼠肝细胞线粒体形态结构显著改善、血清AST水平显著下降（

=4.879，

=14，95%

：-47.24~-18.39，

=0.000 2）。⑨在低氧寒冷环境暴露（5 800 m、6 ℃、24 h）后，与H组相比，H+V组大鼠皮下白色脂肪组织中UCP1蛋白水平显著增加（

=2.26，

=10，95%

：0.849~118.1，

=0.047）。

结论

慢性低氧暴露可促使肝脏ANGPTL3水平增加并释放入血，进而通过损伤肝细胞线粒体以及抑制白色脂肪棕色化潜能，导致耐寒能力下降。

Abstract

Objective

To investigate the role and mechanism of hepatic-derived angiopoietin-like 3 (ANGPTL3) in mediating reduced cold tolerance induced by chronic hypoxic exposure.

Methods

① Male Sprague-Dawley (SD) rats (7 to 8 weeks old

weighing 220 to 260 g) were randomly divided into a normoxic group (N

housed at an ambient condition of altitude 308 m and 24.0±0.5 ℃) and a hypoxic group (H

housed in a hypobaric hypoxic chamber of simulating an altitude 5 800 m and 24.0±0.5 ℃)

with 20 rats in each group. Twelve rats from each group were implanted intraperitoneally with temperature-sensing transponders for subsequent measurement of core body temperature (Tc). ② Male SD rats were randomly divided into (

=20 per group): a hypoxic (H) group and a hypoxic+ANGPTL3 inhibitor [Vupanorsen 2 mg/(kg·w)

]

intervention (H+V) group. Twelve rats from each group were implanted intraperitoneally with temperature-sensing transponders for subsequent Tc measurement. The rats in the H and H+V groups were all housed in a hypobaric hypoxic chamber (simulated altitude 5 800 m

24.0±0.5 ℃). After 6 weeks

8 non-implanted rats per group were anesthetized for blood and liver tissue collection. Serum aspartate aminotransferase (AST) level was measured using an automatic biochemical analyzer. Blood levels of hepatic factors were detected with ELISA. Hepatic mitochondrial morphology was assessed by transmission electron microscopy (TEM). Hepatic ANGPTL3 protein level was quantified by Western blotting. The 12 implanted rats from each group were exposed to either a hypoxic cold environment (5 800 m

6 ℃ for 24 h) or a normoxic cold environment (308 m

-10 ℃ for 6 h). Tc was monitored using a physiological signal telemetry system to assess cold tolerance. Western blotting was used to detect the protein level uncoupling protein 1 (UCP1) in subcutaneous white adipose tissue as an indicator of browning potential.

Results

① Compared to normothermic hypoxia (5 800 m

24 ℃)

the group H exhibited a significant Tc decrease during hypoxic cold exposure (5 800 m

6 ℃) (

0.05). ② During normoxic cold exposure (308 m

-10 ℃

6 h)

Tc was significantly decreased in both groups N and H

and it was obviously lower in the group H than the group N (

0.05). ③ Compared to the N group

serum ANGPTL3 level (

=7.3

=10

95%

: 2.553 to 2.687

0.000 1) and hepatic ANGPTL3 protein level (

=6.532

=10

95%

: 26.98 to 54.92

0.000 1) were notably elevated in the group H. ④ Compared to the H group

serum ANGPTL3 level (

=7.803

df=10

95%

: -196.8 to -109.4

=0.000 4) and hepatic ANGPTL3 protein level (

=3.514

=10

95%

: -66.14 to -14.81.

=0.006) were remarkably decreased in the group H+V. ⑤ During normoxic cold exposure (308 m

-10 ℃

6 h)

Tc was significantly decreased in both groups H and H+V

with that of the group H+V significantly higher that of the group H (95%

: -0.629 to -0.452

=0.000 4). ⑥ Under hypoxic cold exposure (5 800 m

6 ℃

24 h)

Tc was decreased significantly in both groups H and H+V

with that in the H+V group higher than that of the group H (95%

: -0.568 to -4.431

=0.018 1). ⑦ Compared to the N group

hepatocyte mitochondrial morphology was significantly damaged and serum AST level was significantly increased (

=14.15

=14

95%

:51.61 to 70.04

0.000 1) in the group H. ⑧ Compared to the group H

hepatocyte mitochondrial morphology was significantly improved and the serum AST level was significantly decreased (

=4.879

=14

95%

: -47.24 to -18.39

=0.000 2) in the group H+V. ⑨ Following hypoxic cold exposure (5 800 m

6 ℃

24 h)

the protein level of UCP1 in subcutaneous white adipose tissue was significantly increased in the group H+V than the group H (

=2.26

=10

95%

: 0.849 to 118.1

=0.047).

Conclusion

Chronic hypoxic exposure increases hepatic ANGPTL3 production and release into blood circulation

subsequently impairing cold tolerance. This effect is mediated through ANGPTL3-induced hepatic mitochondrial damage and suppression of white adipose tissue browning potential.

关键词

Keywords

references

LI M Q ， TANG X P ， LIAO Z Y ， et al . Hypoxia and low temperature upregulate transferrin to induce hypercoagulability at high altitude ［J］. Blood ， 2022 ， 140 （ 19 ）： 2063 - 2075 . DOI： 10.1182/blood.2022016410 http://dx.doi.org/10.1182/blood.2022016410 .

郑媛媛，唐玲芳，谢华，等 . 中药外用制剂在高原官兵常见皮肤病防治中的应用［J］. 联勤军事医学， 2024 ， 38 （ 7 ）： 631 - 636 . DOI： 10.13730/j.issn.2097-2148.2024.07.019 http://dx.doi.org/10.13730/j.issn.2097-2148.2024.07.019 .

ZHENG Y Y ， TANG L F ， XIE H ， et al . Application of external preparation of traditional Chinese medicine in prevention and treatment of common dermatoses in plateau officers and soldiers ［J］. Mil Med Jt Logist ， 2024 ， 38 （ 7 ）： 631 - 636 . DOI： 10.13730/j.issn.2097-2148.2024.07.019 http://dx.doi.org/10.13730/j.issn.2097-2148.2024.07.019 .

KOUNALAKIS S N ， KERAMIDAS M E ， AMON M ， et al . A 10-day confinement to normobaric hypoxia impairs toe， but not finger temperature response during local cold stress ［J］. J Therm Biol ， 2017 ， 64 ： 109 - 115 . DOI： 10.1016/j.jtherbio. 2017.01.009 http://dx.doi.org/10.1016/j.jtherbio.2017.01.009 .

ABUMRAD N A . The liver as a hub in thermogenesis ［J］. Cell Metab ， 2017 ， 26 （ 3 ）： 454 - 455 . DOI： 10.1016/j.cmet.2017. 08.018 http://dx.doi.org/10.1016/j.cmet.2017.08.018 .

TSUTSUMI T ， NAKANO D ， HASHIDA R ， et al . The inter-organ crosstalk reveals an inevitable link between MAFLD and extrahepatic diseases ［J］. Nutrients ， 2023 ， 15 （ 5 ）： 1123 . DOI： 10.3390/nu15051123 http://dx.doi.org/10.3390/nu15051123 .

刘伟丽，蒲玲玲，徐洪宝，等 . 高原某部军人驻守不同时间血清生化指标分析［J］. 解放军预防医学杂志， 2020 ， 38 （ 10 ）： 6 - 8 . DOI： 10.13704/j.cnki.jyyx.2020.10.003 http://dx.doi.org/10.13704/j.cnki.jyyx.2020.10.003 .

LIU W L ， PU L L ， XU H B ， et al . Analysis of serum biochemical indexes of soldiers stationed at different time in plateau ［J］. J Prev Med Chin PLA ， 2020 ， 38 （ 10 ）： 6 - 8 . DOI： 10.13704/j.cnki.jyyx.2020.10.003 http://dx.doi.org/10.13704/j.cnki.jyyx.2020.10.003 .

祁生贵，更登，李莉，等 . 非酒精性脂肪性肝病在不同海拔及不同民族人群中的患病率［J］. 环境卫生学杂志， 2022 ， 12 （ 7 ）： 533 - 536 . DOI： 10.13421/j.cnki.hjwsxzz.2022.07.011 http://dx.doi.org/10.13421/j.cnki.hjwsxzz.2022.07.011 .

QI S G ， GENG D ， LI L ， et al . The incidence rate for nonalcoholic fatty liver disease in the different ethnic population at high altitude ［J］. J Environ Hyg ， 2022 ， 12 （ 7 ）： 533 - 536 . DOI： 10.13421/j.cnki.hjwsxzz.2022.07.011 http://dx.doi.org/10.13421/j.cnki.hjwsxzz.2022.07.011 .

HUANG Y J ， DING Y ， GUO X Y ， et al . Chronic hypoxia induces liver injury via PKCδ/ASMase-driven ceramide accumulation and endoplasmic reticulum stress in rats ［J］. Lipids Health Dis ， 2025 ， 24 （ 1 ）： 312 . DOI： 10.1186/s12944-025-02761-w http://dx.doi.org/10.1186/s12944-025-02761-w .

SIMCOX J ， GEOGHEGAN G ， MASCHEK J A ， et al . Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis ［J］. Cell Metab ， 2017 ， 26 （ 3 ）： 509 - 522.e6 . DOI： 10.1016/j.cmet.2017.08.006 http://dx.doi.org/10.1016/j.cmet.2017.08.006 .

GAUDET D ， KARWATOWSKA-PROKOPCZUK E ， BAUM S J ， et al . Vupanorsen， an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA， lowers triglycerides and atherogenic lipoproteins in patients with diabetes， hepatic steatosis， and hypertriglyceridaemia ［J］. Eur Heart J ， 2020 ， 41 （ 40 ）： 3936 - 3945 . DOI： 10.1093/eurheartj/ehaa689 http://dx.doi.org/10.1093/eurheartj/ehaa689 .

荣黎，曾维政，吴晓玲 . 高原缺氧与肝脏损伤［J］. 世界华人消化杂志， 2009 ， 17 （ 21 ）： 2171 - 2178 . DOI： 10.3969/j.issn.1009-3079.2009.21.010 http://dx.doi.org/10.3969/j.issn.1009-3079.2009.21.010 .

RONG L ， ZENG W Z ， WU X L . High altitude hypoxia and liver injury ［J］. World Chin J Dig ， 2009 ， 17 （ 21 ）： 2171 - 2178 . DOI： 10.3969/j.issn.1009-3079.2009.21.010 http://dx.doi.org/10.3969/j.issn.1009-3079.2009.21.010 .

CAO Y ， WANG Y C ， ZHOU Z Q ， et al . Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure ［J］. Science ， 2022 ， 377 （ 6613 ）： 1399 - 1406 . DOI： 10.1126/science.abn0910 http://dx.doi.org/10.1126/science.abn0910 .

LIM S ， TASKINEN M R ， BORÉN J . Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome ［J］. Obes Rev ， 2019 ， 20 （ 4 ）： 599 - 611 . DOI： 10.1111/obr.12820 http://dx.doi.org/10.1111/obr.12820 .

SUZUKI K ， CLAGGETT B ， MINAMISAWA M ， et al . Liver function and prognosis， and influence of sacubitril/valsartan in patients with heart failure with reduced ejection fraction ［J］. Eur J Heart Fail ， 2020 ， 22 （ 9 ）： 1662 - 1671 . DOI： 10.1002/ejhf.1853 http://dx.doi.org/10.1002/ejhf.1853 .

NJOKU D B ， SCHILLING J D ， FINCK B N . Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy： key roles for liver-heart crosstalk ［J］. Curr Opin Lipidol ， 2022 ， 33 （ 5 ）： 295 - 299 . DOI： 10.1097/MOL.0000000000000845 http://dx.doi.org/10.1097/MOL.0000000000000845 .

CAI G X ， LIU J J ， WANG M B ， et al . Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension ［J］. Exp Biol Med （Maywood）， 2019 ， 244 （ 3 ）： 252 - 261 . DOI： 10.1177/1535370219828692 http://dx.doi.org/10.1177/1535370219828692 .

ROYO F ， MORENO L ， MLECZKO J ， et al . Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism ［J］. Sci Rep ， 2017 ， 7 ： 42798 . DOI： 10.1038/srep42798 http://dx.doi.org/10.1038/srep42798 .

MACHADO S A ， PASQUARELLI-DO-NASCIMENTO G ， SANTOS DA SILVA D ， et al . Browning of the white adipose tissue regulation： new insights into nutritional and metabolic relevance in health and diseases ［J］. Nutr Metab ， 2022 ， 19 （ 1 ）： 61 . DOI： 10.1186/s12986-022-00694-0 http://dx.doi.org/10.1186/s12986-022-00694-0 .

UM J H ， PARK S Y ， HUR J H ， et al . Bone morphogenic protein 9 is a novel thermogenic hepatokine secreted in response to cold exposure ［J］. Metabolism ， 2022 ， 129 ： 155139 . DOI： 10.1016/j.metabol.2022.155139 http://dx.doi.org/10.1016/j.metabol.2022.155139 .

LV S H ， ZHOU Y Q ， CHEN J J ， et al . Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade ［J］. Cell Rep ， 2022 ， 40 （ 13 ）： 111422 . DOI： 10.1016/j.celrep.2022.111422 http://dx.doi.org/10.1016/j.celrep.2022.111422 .

SUI Y ， CHEN J P . Hepatic FGF21： its emerging role in inter-organ crosstalk and cancers ［J］. Int J Biol Sci ， 2022 ， 18 （ 15 ）： 5928 - 5942 . DOI： 10.7150/ijbs.76924 http://dx.doi.org/10.7150/ijbs.76924 .

CUEVAS-RAMOS D ， MEHTA R ， AGUILAR-SALINAS C A . Fibroblast growth factor 21 and browning of white adipose tissue ［J］. Front Physiol ， 2019 ， 10 ： 37 . DOI： 10.3389/fphys.2019.00037 http://dx.doi.org/10.3389/fphys.2019.00037 .

HU X Z ， FAN J J ， MA Q Q ， et al . A novel nanobody-heavy chain antibody against angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease ［J］. J Nanobiotechnology ， 2022 ， 20 （ 1 ）： 237 . DOI： 10.1186/s12951-022-01456-z http://dx.doi.org/10.1186/s12951-022-01456-z .

ZHANG Y J ， YAN C ， DONG Y ， et al . ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque ［J］. J Adv Res ， 2025 ， 70 ： 125 - 138 . DOI： 10.1016/j.jare.2024.05.011 http://dx.doi.org/10.1016/j.jare.2024.05.011 .

WATTS G F ， SCHWABE C ， SCOTT R ， et al . RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering： phase 1 basket trial cohorts ［J］. Nat Med ， 2023 ， 29 （ 9 ）： 2216 - 2223 . DOI： 10.1038/s41591-023-02494-2 http://dx.doi.org/10.1038/s41591-023-02494-2 .

LUO F ， DAS A ， KHETARPAL S A ， et al . ANGPTL3 inhibition， dyslipidemia， and cardiovascular diseases ［J］. Trends Cardiovasc Med ， 2024 ， 34 （ 4 ）： 215 - 222 . DOI： 10.1016/j.tcm.2023.01.008 http://dx.doi.org/10.1016/j.tcm.2023.01.008 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Hypoxia induced non-concordant expression of gastrocnemius mitochondrial electron transport chain complexes in Wistar rats

Mdivi-1 improves cognitive dysfunction in immature SD rats induced by hypoxia combined with propofol by inhibiting excessive mitophagy

Molecular mechanism of hypoxia-induced spermatogenesis impairment by inhibiting the stability of sperm cilial microtubules

Plateau hypoxia improves tumor immune microenvironment and inhibits subcutaneous tumor growth of colorectal cancer

Protective effect of equol on mitochondrial damage induced by high glucose and fat in osteoblasts

Related Author

高文祥

黄缄

高钰琪

谭小玲

刘福玉

蔡明春

陈建

XU Yao

Related Institution

Department of Anesthesiology Children’s Hospital of Chongqing Medical University， National Clinical Research Center for Child Health and Disorders， Ministry of Education Key Laboratory of Child Development and Disorders， Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders

Department of Pathophysiology， Key Laboratory of High Altitude Medicine， Key Laboratory of Extreme Environmental Medicine of Ministry of Education， Faculty of High Altitude Military Medicine， Army Medical University （Third Military Medical University）

Department of Pathophysiology， Key Laboratory of Extreme Environmental Medicine of Ministry of Education， Faculty of High Altitude Military Medicine， Army Medical University （Third Military Medical University）

⁰

Chronic hypoxia reduces cold tolerance via hepatic ANGPTL3-driven mitochondrial damage and adipose thermogenesis suppression

DOI：10.16016/j.2097-0927.202510098

摘要

Abstract

关键词

Keywords

references