E4BP4 is an insulin-induced stabilizer of nuclear SREBP-1c and promotes SREBP-1c-mediated lipogenesis

Tong, Xin; Li, Pei; Zhang, Deqiang; VanDommelen, Kyle; Gupta, Neil; Rui, Liangyou; Omary, M. Bishr; Yin, Lei

doi:10.1194/jlr.m067181

Cited by 20 publications

(16 citation statements)

References 64 publications

(77 reference statements)

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“…Isolation of primary mouse hepatocytes (PMHs) was described previously. 27 PMHs and Hepa1 cells were treated with DMSO and 5 μM tunicamycin for 24 hours and harvested for western blotting, RT-qPCR, and BODIPY staining.…”

Section: Cell Culturesmentioning

confidence: 99%

“…We previously reported that insulin induces the E4bp4 expression via an SREBP-1c-dependent manner and such an induction is critical for de novo lipogenesis in hepatocytes. 27 Whether the E4bp4 expression is also sensitive to other lipogenic stimuli remains unknown. A recent study reported that the ER stress inducer tunicamycin increases the E4bp4 expression in pancreatic β-cells and impairs β-cell metabolism and insulin secretion.…”

Section: E4bp4 Is a Novel Target Induced By Er Stress In Hepatocytesmentioning

confidence: 99%

“…We previously reported that the E-box element within the proximal region of the E4bp4 promoter is important for its activation by SREBP-1c. 27 Thus, we tested whether this response element is also required for the CHOP-mediated induction by generating a mutant reporter construct with the deletion of the E-box element. As shown in Figure 3D, Chop overexpression was only able to activate the E4bp4-WT-luc but not the E4pb4-ΔE-box-luc mutant, suggesting that this E-box element is indeed critical for the transcriptional activation of E4bp4 by CHOP ( Figure 3D).…”

Section: Chop Is Partially Required For Tunicamycin-induced E4bp4 Ementioning

confidence: 99%

“…5 We previously reported that E4BP4 mediates de novo lipogenesis downstream of the insulin signaling in hepatocytes. 27 To test whether E4BP4 is involved in the tunicamycin-induced lipid accumulation in hepatocytes and the liver, we generated E4bp4 liver-specific knockout (E4bp4-LKO) mice by crossing E4bp4 flox/flox mice with Alb-Cre transgenic mice and validated the liver-specific deletion of E4BP4 ( Figure 4A). Next, we challenged both E4bp4 flox/flox and E4bp4-LKO PMHs with tunicamycin, and analyzed the impact of E4bp4 deficiency on lipid droplet formation and TG content in hepatocytes.…”

Section: Induced Lipid Droplet Accumulation In Cultured Hepatocytesmentioning

confidence: 99%

“…We previously reported that potent induction of E4BP4 by insulin contributes to the postprandial de novo lipogenesis in an SREBP-1c-dependent manner. 27 E4bp4deficient hepatocytes exhibit a significant reduction in de novo lipogenesis, triglyceride content as well as the expression of lipogenic enzymes including Fasn and Scd1. The work from the Zhang group shows that E4BP4 could impact hepatic lipid metabolism via its interaction with CREBH, a liver-enriched ER-tethered transcription factor known to regulate hepatic lipid homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic E4BP4 induction promotes lipid accumulation by suppressing AMPK signaling in response to chemical or diet‐induced ER stress

et al. 2020

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Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non‐alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b‐ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high‐fat, low‐methionine, and choline‐deficient (HFLMCD) diet. We showed that such an induction is partially dependent on CHOP, a known mediator of ER stress and requires the E‐box element of the E4bp4 promoter. Tunicamycin promotes the lipid droplet formation and alters lipid metabolic gene expression in primary mouse hepatocytes from E4bp4flox/flox but not E4bp4 liver‐specific KO (E4bp4‐LKO) mice. Compared with E4bp4flox/flox mice, E4bp4‐LKO female mice exhibit reduced liver lipid accumulation and partially improved liver function after 10‐week HFLMCD diet feeding. Mechanistically, we observed elevated AMPK activity and the AMPKβ1 abundance in the liver of E4bp4‐LKO mice. We have evidence supporting that E4BP4 may suppress the AMPK activity via promoting the AMPKβ1 ubiquitination and degradation. Furthermore, acute depletion of the Ampkβ1 subunit restores lipid droplet formation in E4bp4‐LKO primary mouse hepatocytes. Our study highlighted hepatic E4BP4 as a key factor linking ER stress and lipid accumulation in the liver. Targeting E4BP4 in the liver may be a novel therapeutic avenue for treating NAFLD.

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Section: Cell Culturesmentioning

confidence: 99%

Section: E4bp4 Is a Novel Target Induced By Er Stress In Hepatocytesmentioning

confidence: 99%

Section: Chop Is Partially Required For Tunicamycin-induced E4bp4 Ementioning

confidence: 99%

Section: Induced Lipid Droplet Accumulation In Cultured Hepatocytesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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