Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis

This research was originally published in the Journal of Biological Chemistry. An Zou, Nancy Magee, Fengyan Deng, Sarah Lehn, Cuncong Zhong, Yuxia Zhang. Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. J. Biol. Chem. 2018; Vol:pp-pp. © The American Society for Biochemistry and Molecular Biology. This work is licensed under a Creative Commons Attribution 4.0 International License.Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro, we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun–mediated transcriptional repression of Shp. Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C–C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH

Thalamic Ventral Intermediate Nucleus Deep Brain Stimulation for Orthostatic Tremor

Background: Orthostatic tremor (OT) was first described in 1977. It is characterized by rapid tremor of 13–18 Hz and can be recorded in the lower limbs and trunk muscles. OT remains difficult to treat, although some success has been reported with deep brain stimulation (DBS). Case Report: We report a 68-year-old male with OT who did not improve significantly after bilateral thalamic stimulation. Discussion: Although some patients were described who improved after DBS surgery, more information is needed about the effect of these treatment modalities on OT, ideally in the form of randomized trial data

Tracking Parkinson's : Study Design and Baseline Patient Data

Peer reviewedPublisher PD

Metformin Increases Natural Killer Cell Functions in Head and Neck Squamous Cell Carcinoma Through CXCL1 Inhibition

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692). METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses. RESULTS: Increased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1. CONCLUSIONS: Our data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC

Effects of Toxoplasma gondii growth in host cells that overexpress the gene CYP17

Toxoplasma gondii (T. gondii) is a parasitic protozoa that can infect all mammal including humans. Humans can ingest Toxoplasma by eating undercooked meat or by exposure to cat feces. T. gondii can cause birth defects, encephalitis, and more recently has been shown to cause behavior alteration in the chronic stage of infection. Recently a cell base screening determined that when the gene CYP17 was overexpressed, T. gondii grew at an increased rate. CYP17 codes for an enzyme involved in the cholesterol biosynthesis pathway. To determine the mechanism of increased parasite growth, host cells have been created to express an inserted copy of CYP17. The created cell lines will be tested against wildtype human cells in three separate experiments. These experiments will test the rate of parasite invasion into host cells, intracellular growth and egress. The outcomes of these experiments will determine at what stage of growth CYP17 overexpression most affects

New Insights into Orphan Nuclear Receptor SHP in Liver Cancer

Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP's gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP's antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease

Refractory epilepsy secondary to anti-GAD encephalitis treated with DBS post SEEG evaluation: a novel case report based on stimulation findings

We report a case of medically refractory anti-GAD encephalitis which was treated with deep brain stimulation (DBS) after seizure termination was achieved using cortical stimulation during stereo-electroencephalography (SEEG) evaluation. The patient underwent bilateral SEEG implantation and cortical stimulation. Upon stimulation, mimicking the intrinsic seizures (at 1Hz), it was possible to induce seizures with typical semiology, on multiple attempts. Stimulation during these seizures with high frequency (50Hz) resulted in complete termination of the seizure. DBS was inserted after the SEEG evaluation, targeting the bilateral anterior nucleus of the thalamus. There was a sustained reduction in seizure frequency and severity 12 months post insertion. There were also improvements in quality of life. To the best of our knowledge, this is the only case reported in which DBS was successfully used to treat refractory epilepsy in a patient with seizures that were proven to be responsive to electrical stimulation during SEEG recording