In mammals, endoplasmic reticulum (ER) stress, oxidative stress, and inflammatory responses compose the major defense networks that help the cells adapt to and survive stress conditions caused by biochemical, physiological and pathological stimuli. However, chronic ER stress, oxidative stress, or inflammation have been found to be associated with the initiation and progression of a variety of human diseases in the modern world. Under many pathophysiologic conditions, ER stress response, oxidative stress, and inflammatory responses are integrated and amplified in specialized cell types to facilitate the progression of disease. In the past few decades, ER stress response, oxidative stress, and inflammation as well as their interactive relationships have been hot research topics in biomedicine. In this review, we summarize the recent advance in our understanding of the cross talk between ER stress response, oxidative stress, and inflammation in immunity and in inflammatory and metabolic diseases.

Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes. In this study, we demonstrated that the liver-enriched transcription factor CREBH (cAMP-responsive element binding protein, hepatocyte specific) and peroxisome proliferator-activated receptor α (PPARα) function as binary transcriptional activators to regulate lipid metabolism by activating fibroblast growth factor 21 (FGF21), a hepatic hormone that regulates whole-body energy homeostasis. Gain- and loss-of-function studies indicated that CREBH regulates triglyceride and fatty acid metabolism in animals under fasting or on an atherogenic high-fat (AHF) diet. CREBH and PPARα act as interactive trans-activators that regulate each other for their expression. Activated CREBH protein interacts with PPARα to form a functional complex upon fasting or the AHF diet, and both factors are required for induction of the metabolic hormone FGF21. The CREBH-PPARα complex was found to bind to integrated CRE-PPAR-responsive element-binding motifs in the FGF21 gene promoter. Whereas CREBH and PPARα function in synergy to activate FGF21 gene expression, PPARα relies on CREBH to exert its trans-activation effect on FGF21. Supporting the key role of CREBH in regulating FGF21, infusion of recombinant FGF21 protein can reverse hypertriglyceridemia and hypoketonemia and partially rescue nonalcoholic steatohepatitis developed in the CREBH-null mice after the AHF diet. Our study demonstrated a transcriptional regulatory axis of CREBH-PPARα-FGF21 in maintaining lipid homeostasis under metabolic stress. The functional relationship between CREBH and PPARα in regulating FGF21 may represent an important transcriptional coactivation mechanism that orchestrates the processes of energy supply upon metabolic alteration.

Endoplasmic reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded proteins in the ER lumen, which is known to activate an intracellular stress signaling termed Unfolded Protein Response (UPR). A number of pharmacologic reagents or pathophysiologic stimuli can induce ER stress and activation of the UPR signaling, leading to alteration of cell physiology that is associated with the initiation and progression of a variety of diseases. Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation, has been considered the precursor or the hepatic manifestation of metabolic disease. In this study, we delineated the toxic effect and molecular basis by which pharmacologic ER stress, induced by a bacterial nucleoside antibiotic tunicamycin (TM), promotes NASH in an animal model. Mice of C57BL/6J strain background were challenged with pharmacologic ER stress by intraperitoneal injection of TM. Upon TM injection, mice exhibited a quick NASH state characterized by hepatic steatosis and inflammation. An increase in hepatic triglycerides (TG) and a decrease in plasma lipids, including plasma TG, plasma cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), were observed in the TM-treated mice. In response to TM challenge, cleavage of sterol responsive binding protein (SREBP)-1a and SREBP-1c, the key trans-activators for lipid and sterol biosynthesis, was dramatically increased in the liver. Consistent with the hepatic steatosis phenotype, expression of some key regulators and enzymes in de novo lipogenesis and lipid droplet formation was up-regulated, while expression of those involved in lipolysis and fatty acid oxidation was down-regulated in the liver of mice challenged with TM. Moreover, TM treatment significantly increased phosphorylation of NF-κB inhibitors (IκB), leading to the activation of NF-κB-mediated inflammatory pathway in the liver. Our study not only confirmed that pharmacologic ER stress is a strong “hit” that triggers NASH, but also demonstrated crucial molecular links between ER stress, lipid metabolism, and inflammation in the liver in vivo.

The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)–tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator–activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.

Abstract The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.