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Clinical Trial
. 2017 Apr 19:8:15010.
doi: 10.1038/ncomms15010.

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport

Alexander Bartelt  1   2   3 , Clara John  1 , Nicola Schaltenberg  1 , Jimmy F P Berbée  4 , Anna Worthmann  1 , M Lisa Cherradi  1 , Christian Schlein  1 , Julia Piepenburg  1 , Mariëtte R Boon  4 , Franz Rinninger  5 , Markus Heine  1 , Klaus Toedter  1 , Andreas Niemeier  2 , Stefan K Nilsson  1   6 , Markus Fischer  7 , Sander L Wijers  8 , Wouter van Marken Lichtenbelt  8 , Ludger Scheja  1 , Patrick C N Rensen  4 , Joerg Heeren  1
Affiliations
Clinical Trial

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport

Alexander Bartelt et al. Nat Commun. .

Abstract

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Atheroprotective effects of thermogenic adipocytes are linked to plasma HDL-cholesterol.
(a) Fasting plasma HDL-cholesterol were measured in Western-type diet-fed female E3L.CETP mice at the indicated time points during treatment with CL316,243 (CL) or vehicle (control; *P<0.05 determined by Student's t-test, n≥13). (b) Correlation of HDL-cholesterol levels in E3L.CETP mice with atherosclerotic plaque size after CL treatment. Values in a are means±s.e.m. (n≥13 per group). *P<0.05 (a,b: univariate regression analysis).
Figure 2
Figure 2. Thermogenic adipocytes modulate TRL and HDL levels in normo- and hyperlipidemic mice.
Mice were either mock-treated (Mock), exposed to 4 °C (Cold) or treated with CL316,243 (CL) for 7 days. (a) Total plasma TG and (b) cholesterol as well as (c–h) corresponding cholesterol FPLC profiles from plasma of (c,f) C57BL/6J, (d,g) Apoa5−/− and (e,h) E3L.CETP mice. For FPLC analysis, individual plasma samples were analysed and cholesterol levels were determined n each fraction (n=4–5 per group). Values are means±s.e.m. Significance was calculated using unpaired two-tailed Student's t-test. *P<0.05, versus mock.
Figure 3
Figure 3. Thermogenic activation causes characteristic HDL lipidome remodelling.
Lipidomic analysis of HDL from (a,c,e) Apoa5−/− and (b,d,f) E3L.CETP mice after 7 days of CL or cold treatment. Changes in (a,b) PC, (c,d) Lyso-PC, (e,f) CE species relative to mock-treated mice, determined by high-resolution mass spectrometry, are represented as per cent weight changes relative to the whole-lipid class. For example, a 5% change in a PC species translates to, for example, 20% abundance of this lipid to 25% of total PC. Calculated values are mean±s.e.m. (n=4-5 per group). Post hoc correction for multiple testing was performed using the Benjamini–Hochberg method for the number of lipids shown. *P<0.05, **P<0.01, ***P<0.001, versus mock (Student's t-test).
Figure 4
Figure 4. Cold exposure induces HDL lipidome remodelling in humans.
Plasma lipoprotein profiles determined by FPLC in (a) 9 lean and (b) 10 obese humans before and after 2 day-treatment with cold. Changes in (c) PC, (d) lyso-PC and (e) CE species in HDL from cold-treated individuals relative to their baseline levels are represented as per cent weight changes of total lipid class. Calculated values are mean±s.e.m. (n=9–10 per group). Post hoc correction for multiple testing was performed using the Benjamini–Hochberg method for the number of lipids shown.*P<0.05, **P<0.01, versus mock (Student's t-test).
Figure 5
Figure 5. Thermogenic adipocytes promote reverse cholesterol transport without altering cholesterol efflux capacity of HDL.
Serum and HDL were prepared from wild-type C57BL/6J mice housed at thermoneutrality (mock), at 4 °C (cold) or treated with CL for 7 days. Peritoneal macrophages were pre-loaded with 3H-cholesterol and specific cholesterol efflux was induced (a) in the absence (control) or in the presence of 2% serum for the indicated time or (b) in the absence (IM=incubation medium) or in the presence of 2% serum or 50 μg ml−1 HDL for 4 h at 37 °C. Values are mean±s.e.m. of n=3 independent experiments. *P<0.05, versus mock (Student's t-test). For metabolic turnover studies, HDL from untreated (mock-HDL) or CL-treated (CL-HDL) wild-type C57BL/6J mice were radiolabelled. After injection of 125I-protein shell- and 3H-cholesterol oleoyl ether core-radiolabelled HDL, (c) plasma clearance and (d) liver uptake of 3H-cholesterol oleoyl ether were determined. Values are mean±s.e.m. (n=7 per group). In vivo RCT assay in thermoneutral (mock), CL-treated and cold-exposed (e–g) C57BL/6J and (h–j) E3L.CETP mice after the injection of peritoneal macrophages, ex vivo loaded with LDL and 3H-cholesterol. Radioactivity was determined 48 h after macrophage injection (e,h) in plasma and (f,i) in liver as well as (g,j) 24 h and 48 h after macrophage injection in faeces. Values are mean±s.e.m. (n=8–10 per group).*P<0.05, **P<0.01, ***P<0.001, versus mock (Student's t-test).
Figure 6
Figure 6. Lipolysis by LPL and hepatic SR-BI increase cold-induced HDL turnover.
125I-protein shell- and 3H-cholesteryl oleoyl ether (CEt) core-radiolabelled HDL were injected into (a–c) fasted and (d–f) re-fed C57BL/6J mice, which had been either cold-exposed for 7 days (cold) or kept under thermoneutral conditions (warm). Double-labelled HDL were also injected into fasted mice cold-adapted for 7 days with (g–i) adipocyte-specific LPL knockout (aLKO) and (j–l) Scarb1−/− mice and wild-type (WT) controls. HDL-derived 3H-CEt clearance from plasma was analysed at indicated time points by determining (a,d,g,j) total and (b,e,h,k) selective clearance. Values for selective clearance are presented as the ratio of 3H/125I radioactivity and calculated for each time point indicated (an accelerated selective HDL-cholesterol clearance from plasma is indicated by a lower ratio of 3H/125I while impaired plasma clearance leads to higher 3H/125I). (c,f,i,l) The organ uptake of HDL-3H-CEt was measured 5 h after injection of radiolabelled HDL. gWAT, gonadal WAT; iWAT, inguinal WAT; iBAT, interscapular BAT. Values are mean±s.e.m. (n=5-7 per group). *P<0.05, **P<0.01, ***P<0.001, versus control (Student's t-test).
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