Physiological Responses to Hypoxia on Triglyceride Levels

Abstract

Hypoxia is a condition during which the body or specific tissues are deprived of oxygen. This phenomenon can occur in response to exposure to hypoxic environmental conditions such as high-altitude, or because of pathophysiological conditions such as obstructive sleep apnea. Circumstances such as these can restrict supply or increase consumption of oxygen, leading to oxyhemoglobin desaturation and tissue hypoxia. In certain cases, hypoxia may lead to severe health consequences such as an increased risk of developing cardiovascular diseases and type 2 diabetes. A potential explanation for the link between hypoxia and an increased risk of developing cardiovascular diseases lies in the disturbing effect of hypoxia on circulating blood lipids, specifically its capacity to increase plasma triglyceride concentrations. Increased circulating triglyceride levels result from the production of triglyceride-rich lipoproteins, such as very-low-density lipoproteins and chylomicrons, exceeding their clearance rate. Considerable research in murine models reports that hypoxia may have detrimental effects on several aspects of triglyceride metabolism. However, in humans, the mechanisms underlying the disturbing effect of hypoxia on triglyceride levels remain unclear. In this mini-review, we outline the available evidence on the physiological responses to hypoxia and their impact on circulating triglyceride levels. We also discuss mechanisms by which hypoxia affects various organs involved in the metabolism of triglyceride-rich lipoproteins. This information will benefit scientists and clinicians interested in the mechanistic of the regulatory cascade responsible for the response to hypoxia and how this response could lead to a deteriorated lipid profile and an increased risk of developing hypoxia-related health consequences.

Keywords: continuous hypoxia; dyslipidemia; intermittent hypoxia; triglyceride-rich lipoproteins; triglycerides.

FIGURE 1

Potential underlying physiological mechanisms by which hypoxia modulates blood triglyceride levels. Circulating TG levels reflect the production of TRL by both the liver (as VLDL) and the intestine (as CM) as well as the disposal of TRL and their remnants (LDL and CR) in the liver/periphery. Hypoxia does not disturb CM metabolism in the small intestine. Conversely, hypoxia disturbs hepatic and adipose tissue functions by (1) delaying hepatic removal of TRL remnants from circulation, and/or (2) delaying intravascular lipolysis of TRL via the HIF-1 upregulation of ANGTPL4, a potent inhibitor of adipose tissue LPL activity. In the liver, hypoxia also increases lipid biosynthesis via HIF-1-dependent upregulation of the transcriptional factor SREBP-1, which increases expression of SCD-1, the rate-limiting enzyme for the synthesis of MUFA, a major substrate for the synthesis of CE, TG, and PL. These latter substrates are key determinants involved in VLDL production. Through sympathetic activation, hypoxia can also increase VLDL production by (1) directly increasing VLDL assembly in the liver, and/or (2) by stimulating intracellular lipolysis of adipose tissue, which results in the increased release of NEFA, the main precursor to VLDL production. ANGPTL4, Angiopoietin-like 4; CM, Chylomicron; CR, Chylomicron remnant; CE, Cholesterol ester; HIF-1, Hypoxia-inducible factor 1; LDL, Low-density lipoprotein; LPL, Lipoprotein lipase; MUFA, Monounsaturated fatty acid; NEFA, Non-esterified fatty acid; PL, Phospholipid; SCD-1, Stearoyl-CoA desaturase-1; SREBP-1, Sterol regulatory element-binding protein 1; SNS, Sympathetic nervous system; TG, Triglyceride; VLDL, Very-low-density lipoprotein.