CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins
Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt
Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt
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Research Article Endocrinology Metabolism

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins

Abstract

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH’s ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe–/– mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Authors

Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt

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Figure 6

Human subjects with CREB3L3 loss-of-function or missense mutations exhibit increased concentrations of small VLDL and IDL and reduced APOE in LDL/IDL.

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Human subjects with CREB3L3 loss-of-function or missense mutations exhib...
Age-matched human subjects with rare loss-of-function or missense mutations in CREB3L3 and controls with normotriglyceridemia (NTG) were identified. (A) Plasma total cholesterol. (B) Plasma TG levels (logTG). (C) HDL-cholesterol levels. (D–E) VLDL and IDL were separated by density ultracentrifugation (d > 1.019 g/mL) after removal of chylomicrons. Total VLDL and IDL particle concentrations and sizes were measured by calibrated ion mobility analysis. (F–L) Apolipoproteins were quantified in the VLDL+IDL fraction (d < 1.019 g/mL) by targeted mass spectrometry. Data are shown as box-and-whisker plots, with boxes showing 25th to 75th percentile, horizontal lines showing medians, and whiskers showing minimum to maximum. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired, 2-tailed Mann-Whitney test (n = 8 for NTG and n = 10 for subjects with CREB3L3 loss-of-function or missense mutations). (M) Schematic representation of the effects of diabetes and active CREBH on lipoproteins, apolipoproteins, and atherosclerosis. Poorly controlled T1DM results in increased hepatic production of APOC3, which leads to increased APOC3 loading of VLDL and remnants. The increased APOC3 load on VLDL mediates a reduced ability of LPL to hydrolyze VLDL and IDL. Diabetes also suppresses plasma membrane translocation of LRP1, further slowing clearance of remnants and leading to an increased accumulation of remnants in the artery wall, promoting lesion progression. Hepatic CREBH increases hepatic clearance of VLDL and IDL by enhancing the APOE loading of TRL remnants and depleting these particles of APOC3, thereby preventing the effects of diabetes on remnant accumulation and lesion progression (generated with BioRender.com).