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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.

Objectives Interstitial cystitis/bladder pain syndrome (IC/BPS) comprises at least 2 phenotypes. Bladder centric patients typically demonstrate low bladder capacity (BC), often with Hunner lesion (HL), whereas non–bladder-centric patients typically have normal cystoscopic findings and more co-occurring nonurologic symptoms/syndromes (NUS), contributing to widespread pain beyond the bladder. Small fiber polyneuropathy (SFPN) is significantly associated with fibromyalgia, a frequent IC/BPS codiagnosis and may play an etiologic role in IC/BPS. We assessed SFPN status in bladder-centric versus non–bladder-centric IC/BPS patients. Methods Distal leg biopsies were obtained from 11 IC/BPS patients after therapeutic hydrodistention. Specimens were embedded/sectioned per standard protocol and stained for protein gene product 9.5, an intraepidermal nerve fiber marker. To determine SFPN status, intraepidermal nerve fiber density was calculated and compared with normative reference values stratified by age/sex. The SFPN prevalence and reported comorbidities were compared between low BC and/or HL-positive (bladder-centric) versus non–low BC, HL (non–bladder-centric) patients. Results Seven patients (63.6%) were SFPN positive. Non–bladder-centric patients demonstrated significantly more SFPN (6/7, 85.7%) compared with bladder-centric patients (1/4, 25.0%; P = 0.027). Non–bladder-centric patients also reported more comorbid NUS overall (1.25 ± 0.83 vs 5.86 ± 2.47; P = 0.003), including fibromyalgia (P = 0.010), migraines (P = 0.035), anxiety/panic disorder (P = 0.035), allergies (P = 0.027), and asthma (P = 0.035). Conclusions In this pilot study, SFPN was significantly more common in non–bladder-centric IC/BPS, that is, those patients who also reported greater prevalence of NUS, including fibromyalgia, migraines, anxiety/panic disorders, allergies, and asthma. These findings suggest that SFPN may have an etiologic role in a larger, systemic pain syndrome and should be explored further.

Interstitial cystitis/bladder pain syndrome is a poorly understood chronic pain condition. While patients experience chronic pain in their bladders and changes to their urinary habits, they also commonly experience widespread pain and issues beyond their bladder. The cause(s) of these symptoms is not well understood. Our research found evidence that patients with interstitial cystitis commonly have damage/thinning to the nerves in their skin, which is associated with being chronically fatigued. This finding may explain some of the widespread symptoms these patients experience.

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