Hepatocyte Nuclear Factor 4 Alpha Is a Key Factor Related to Depression and Physiological Homeostasis in the Mouse Brain

Abstract

Major depressive disorder (MDD) is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS) as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC) of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a) may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of physiological homeostasis in humans.

Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

“…As in the Patterns, CREB1 was a predicted upstream regulator in PFC, NAc, BLA, and vHIP of genes associated with AI (Figure 5J). HNF4A was also a predicted upstream regulator of genes associated with AI and was one of two upstream regulators (TCF7L2) predicted for both Patterns B and C. HNF4A is implicated in epigenetic mechanisms (49–52) and dendritic spine morphology (51). While expression of Hnf4a was not detected in our sequencing data, other NRs were.…”

Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis

“…Details regarding the experimental animals, the CMS procedure, sample collection, RNA purification, microarray analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and Ingenuity Pathway Analysis (IPA) have been described in our previous studies (18,19).…”

“…Animals were randomly assigned to one of two groups: The control group (C group) mice and the chronic mildly stressed (CMS) group mice, as previously described (18). The procedure to induce CMS is described in Table I and was performed over 4 weeks.…”

“…Total RNA was purified from the mouse brain using a Sepasol-RNA I Super kit (Nacalai Tesque, Inc., Kyoto, Japan), according to the manufacturer's instructions, and was treated with 5 units of RNase-free DNase I at 37˚C for 30 min to remove genomic DNA contamination. Following phenol/chloroform (Wako Pure Chemical Industries, Ltd., Osaka, Japan) extraction and 100% ethanol (Wako Pure Chemical Industries, Ltd.) precipitation, as previously described (18,19), total RNA was dissolved in deionized distilled water. RNA concentrations were determined using a NanoDrop-1000 spectrophotometer (NanoDrop Technologies; Thermo Fisher Scientific, Inc., Pittsburgh, PA, USA).…”

“…The group have previously performed molecular analyses to assess the associations between MDD and dysregulation of physiological homeostasis. Hepatocyte nuclear factor 4α (Hnf4α) was identified as a candidate central regulator that has crucial influence on immunological function, lipid metabolism, coagulation, hormonal activity and the synthesis of amines (18). As Hnf4α is a transcription factor, it is difficult to measure in serum, and the target molecules regulated by Hnf4α that are detectable in serum have not been examined.…”