Very Low Density Lipoprotein Assembly Is Required for cAMP-responsive Element-binding Protein H Processing and Hepatic Apolipoprotein A-IV Expression

Abstract

Hepatic apolipoprotein A-IV (apoA-IV) expression is correlated with hepatic triglyceride (TG) content in mouse models of chronic hepatosteatosis, and steatosis-induced hepatic apoA-IV gene expression is regulated by nuclear transcription factor cAMP-responsive element-binding protein H (CREBH) processing. To define what aspects of TG homeostasis regulate hepatic CREBH processing and apoA-IV gene expression, several mouse models of attenuated VLDL particle assembly were subjected to acute hepatosteatosis induced by an overnight fast or short term ketogenic diet feeding. Compared with chow-fed C57BL/6 mice, fasted or ketogenic diet-fed mice displayed increased hepatic TG content, which was highly correlated (r = 0.95) with apoA-IV gene expression, and secretion of larger, TG-enriched VLDL, despite a lower rate of TG secretion and a similar or reduced rate of apoB100 secretion. When VLDL particle assembly and secretion was inhibited by hepatic shRNA-induced apoB silencing or genetic or pharmacologic reduction in microsomal triglyceride transfer protein (MTP) activity, hepatic TG content increased dramatically; however, CREBH processing and apoA-IV gene expression were attenuated compared with controls. Adenovirus-mediated reconstitution of MTP expression proportionately restored CREBH processing and apoA-IV expression in liver-specific MTP knock-out mice. These results reveal that hepatic TG content, per se, does not regulate CREBH processing. Instead, TG mobilization into the endoplasmic reticulum for nascent VLDL particle assembly activates CREBH processing and enhances apoA-IV gene expression in the setting of acute steatosis. We conclude that VLDL assembly and CREBH activation play key roles in the response to hepatic steatosis by up-regulating apoA-IV and promoting assembly and secretion of larger, more TG-enriched VLDL particles.

Endoplasmic Reticulum Lipid Flux Influences Enterocyte Nuclear Morphology and Lipid-dependent Transcriptional Responses

“…We propose that the reduction in apoA-IV expression that we observe under MTP inhibition is due to a reduction in Creb3l3 processing and activity, as observed by Cheng et al (52). Cheng et al (52) show that TAG flux in the hepatocyte ER controls apoB-VLDL particle assembly, which regulates Creb3l3 proteolytic processing, which in turn promotes the up-regulation of apoA-IV expression to enhance the efficient export of lipid (52). In our hands, MTP inhibition also dampened the responsive expression of plin2 and hmgcs1, key regulators of lipid droplets and TAG processing, respectively (Fig.…”

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

“…ER-anchored CREBH becomes activated in response to hepatic lipid accumulation and VLDL assembly. The activation of CREBH requires ER-to-golgi trafficking followed by proteolytic cleavage and nuclear translocation [ 81 , 83 , 84 ]. CREBH activates a group of genes that are involved in TG and lipoprotein production [ 85 , 86 ].…”

A novel system to quantify intestinal lipid digestion and transport

“…This will destabilize ApoB and it will be degraded, a process in which edem1 and hsp70 are central. ApoAI-V merges with the ApoB-lipid complex mediating expansion of the particle with TG [47], and the particle is transported to the Golgi facilitated by the coatomer complex COPII of which Sar1b is a part [36]. Fatty acids are absorbed by peripheral tissue in the body and a large part of the FAs originating from TG is ß-oxidized in the mitochondria.…”