Dataset Information

Continuous Light Does Not Affect Atherosclerosis in APOE*3-Leiden.CETP Mice.

ABSTRACT: Artificial light exposure is associated with dyslipidemia in humans, which is a major risk factor for the development of atherosclerotic cardiovascular disease. However, it remains unclear whether artificial light at night can exacerbate atherosclerosis. In this study, we exposed female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, to either a regular light-dark cycle or to constant bright light for 14 weeks. Mice exposed to constant light demonstrated a minor reduction in food intake, without any effect on body weight, body composition, or the weight of metabolic organs. Constant light increased the plasma levels of proatherogenic non-high-density lipoprotein (HDL) cholesterol but did not increase the size or severity of atherosclerotic lesions in the aortic root. Mice exposed to constant light did show lower immune cell counts, which could explain the absence of an effect of atherosclerosis despite increased non-HDL cholesterol levels. Behavioral analysis demonstrated variability in the response of mice to the light intervention. Constant light completely blunted behavioral rhythms in some mice, while others extended their behavioral period. However, rhythm strength was not an important determinant of atherosclerosis. Altogether, these results demonstrate that constant bright light does not affect atherosclerosis in APOE*3-Leiden.CETP mice. Whether artificial light exposure contributes to cardiovascular disease risk in humans remains to be investigated.

SUBMITTER: Schilperoort M

PROVIDER: S-EPMC7683885 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Continuous Light Does Not Affect Atherosclerosis in APOE*3-Leiden.CETP Mice.

Schilperoort Maaike M van den Berg Rosa R Coomans Claudia P CP Khedoe Padmini P S J PPSJ Ramkisoensing Ashna A Boekestijn Sanne S Wang Yanan Y Berbée Jimmy F P JFP Meijer Johanna H JH Biermasz Nienke R NR Rensen Patrick C N PCN Kooijman Sander S

Journal of biological rhythms 20200911 6

Artificial light exposure is associated with dyslipidemia in humans, which is a major risk factor for the development of atherosclerotic cardiovascular disease. However, it remains unclear whether artificial light at night can exacerbate atherosclerosis. In this study, we exposed female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, to either a regular light-dark cycle or to constant bright light for 14 weeks. Mice exposed to constant light ...[more]

PMID: 32915671

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Project description:INTRODUCTION: The role of glucocorticoids in atherosclerosis development is not clearly established. Human studies show a clear association between glucocorticoid excess and cardiovascular disease, whereas most animal models indicate an inhibitory effect of glucocorticoids on atherosclerosis development. These animal models, however, neither reflect long-term glucocorticoid overexposure nor display human-like lipoprotein metabolism. AIM: To investigate the effects of transient and continuous glucocorticoid excess on atherosclerosis development in a mouse model with human-like lipoprotein metabolism upon feeding a Western-type diet. METHODS: Pair-housed female APOE*3-Leiden.CETP (E3L.CETP) mice fed a Western-type containing 0.1% cholesterol for 20 weeks were given corticosterone (50 µg/ml) for either 5 (transient group) or 17 weeks (continuous group), or vehicle (control group) in the drinking water. At the end of the study, atherosclerosis severity, lesion area in the aortic root, the number of monocytes adhering to the endothelial wall and macrophage content of the plaque were measured. RESULTS: Corticosterone treatment increased body weight and food intake for the duration of the treatment and increased gonadal and subcutaneous white adipose tissue weight in transient group by +35% and +31%, and in the continuous group by +140% and 110%. Strikingly, both transient and continuous corticosterone treatment decreased total atherosclerotic lesion area by -39% without lowering plasma cholesterol levels. In addition, there was a decrease of -56% in macrophage content of the plaque with continuous corticosterone treatment, and a similar trend was present with the transient treatment. CONCLUSION: Increased corticosterone exposure in mice with human-like lipoprotein metabolism has beneficial, long-lasting effects on atherosclerosis, but negatively affects body fat distribution by promoting fat accumulation in the long-term. This indicates that the increased atherosclerosis observed in humans in states of glucocorticoid excess may not be related to cortisol per se, but might be the result of complex indirect effects of cortisol.

Project description:BackgroundCombined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development.MethodsMale APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day.FindingsGIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury.InterpretationWe interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans.FundingThis work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).

Dataset Information

Continuous Light Does Not Affect Atherosclerosis in APOE*3-Leiden.CETP Mice.

Publications

Continuous Light Does Not Affect Atherosclerosis in APOE*3-Leiden.CETP Mice.

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