Intermittent Hypoxia Induces Hyperlipidemia in Lean Mice

Abstract

Abstract-Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep ob mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity. Key Words: obstructive sleep apnea Ⅲ cholesterol homeostasis Ⅲ lipids Ⅲ hypoxia Ⅲ mouse Ⅲ gene expression O bstructive sleep apnea (SA) is the most common form of sleep-disordered breathing and is characterized by recurrent collapse of the upper airway during sleep, leading to periods of intermittent hypoxia (IH) and sleep fragmentation. 1 SA is present in 2% of women and 4% of men in the general US population, but it is more common in obese individuals. 2,3 SA is an independent risk factor for increased cardiovascular morbidity and mortality. 4 -7 It has been postulated that metabolic dysfunction in SA may provide an intermediate step linking IH and sleep disturbances to cardiovascular disease. Although several recent studies have focused on the effects of SA on dysregulating glucose and insulin metabolism, 2,8 -10 little information is available about the impact of SA on lipid metabolism. Abnormalities in lipid regulation that occur in response to SA may act to increase the cardiovascular risk in an already susceptible population. Although obesity is one of the risk factors for elevations in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels, 11 recent clinical studies indicate that SA may also contribute to hypercholesterolemia. [12][13][14][15] Thus, obesity and IH may interact to alter lipid metabolism in SA.Key steps of lipid metaboli...

Chronic intermittent hypoxia predisposes to liver injury

“…CIH doubled circulating levels of leptin, which was consistent with our previous observations in short-term IH. 11,13,24 Serum corticosterone levels were identical in both groups ( Table 1), suggesting that mice exposed to CIH did not exhibit evidence of stress. CIH resulted in an increase in fasting serum total cholesterol and triglyceride levels ( Table 2), which was similar to our previous observations.…”

“…For measurements of a transcription factor NF-B, a nuclear fraction was isolated as described. 13 Activated NF-B was measured in the nuclear fraction using an ELISA kit from Oxford Biomedical Research. Interleukin-1␤ (IL-1␤), tumor necrosis factor 1␣, and macrophage-inflammatory protein-2 levels in total liver lysate were determined with ELISA kits from R&D Systems, Inc. (Minneapolis, MN).…”

“…2,[4][5][6][7][8][9] Moreover, studies in rodent models of intermittent hypoxia (IH) demonstrated that CIH can cause hypertension, 10 insulin resistance, 11 and dyslipidemia. 12,13 Thus, CIH of OSA has been implicated in causality of cardiovascular and metabolic disorders, independent of obesity.…”

Dyslipidemia: another brick in the wall. A feasible link in the OSA–cardiovascular disease axis

“…Increasing evidence from animal models of OSA shows that intermittent hypoxemia is independently associated with metabolic syndrome, particularly with regard to increase in serum cholesterol and phospholipids, upregulation of pathways of triglyceride and phospholipid biosynthesis and inhibition of mechanisms for cholesterol uptake by the liver [6]. It is a reasonable and compelling consideration that the feasible chain link from OSA to cardiovascular disease (CAD) leads along the pathways through metabolic syndrome (dyslipidemia) (Fig.…”

Obstructive sleep apnea and dyslipidemia: pathophysiological mechanisms

“…However, the point is noted that OSA may be independently associated with insulin resistance and type-2 diabetes as well. Although it has been proposed that induction of phospholipids and triglyceride production by hypoxia-inducible factor (HIF) in the liver is due to sterol regulatory element binding protein-1 (SREBP-1) independent of SREBP-2 which is responsible for cholesterol production via the 3-hydroxy-3-methylglutaryl CoA reductase [3]. However, the mechanisms of HIF and SREBP-1 activation in the liver by chronic intermittent hypoxia from OSA are not completely understood.…”