CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins
Masami Shimizu-Albergine, … , Ira J. Goldberg, Karin E. Bornfeldt
Masami Shimizu-Albergine, … , Ira J. Goldberg, Karin E. Bornfeldt
Published September 7, 2021
Citation Information: J Clin Invest. 2021;131(22):e153285. https://doi.org/10.1172/JCI153285.
View: Text | PDF
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

×

Figure 1

Liver-specific expression of active CREBH induces hepatic expression of genes involved in hepatic clearance of remnant lipoproteins.

Options: View larger image (or click on image) Download as PowerPoint
Liver-specific expression of active CREBH induces hepatic expression of ...
(A) Male Ldlr–/– GpTg mice were fed a high-fat diet (HFD) for 16 weeks, followed by a regular chow to normalize lipids for 1 week. Empty control TGB-AAV-DJ/8 (cAAV, 5 × 1010 GC) or TBG-AAV-DJ/8 containing the active form of mouse CREBH (CREBH AAV, 5 × 1010 GC) was then injected i.v. After 1 week, the mice were rendered diabetic using lymphocytic choriomeningitis virus (LCMV). Saline was used as control in nondiabetic littermates. At the time of LCMV injection, the mice were switched to a low-fat, semipurified diet (LFD) and maintained for an additional 4 weeks after the onset of diabetes. At the end of the study, the liver was collected for measurements of gene expression by real-time PCR (B and D) and liver TG content (C). Plasma was used for measurements of FGF21 (E) and alanine transaminase (ALT) to confirm lack of liver toxicity (F) by ELISA. ND, nondiabetic mice; D, diabetic mice. Mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA (overall effects shown above panels) followed by Tukey’s multiple comparisons test (B, D, and E: n = 17 ND cAAV, n = 16 ND CREBH AAV, n = 18 D cAAV, n = 17 D CREBH AAV; C and F: n = 13 ND cAAV, n = 14 ND CREBH AAV, n = 10 D cAAV, n = 12 D CREBH AAV).