Role of fatty-acid synthesis in dendritic cell generation and function.

Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8(+) T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. CONCLUSION: Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH.

Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver.

BACKGROUND & AIMS: Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other nonpathogens. Dendritic cells (DCs) are believed to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DCs in cancer. Therefore, we investigated whether high lipid content in liver DCs affects induction of tolerance. METHODS: Mouse and human hepatic nonparenchymal cells were isolated by mechanical and enzymatic digestion. DCs were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK) cell, and NKT cell coculture assays as well as in vivo. RESULTS: We observed 2 distinct populations of hepatic DCs in mice and humans based on their lipid content and expression of markers associated with adipogenesis and lipid metabolism. This lipid-based dichotomy in DCs was unique to the liver and specific to DCs compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models; they activated T cells, NK cells, and NKT cells. Conversely, liver DCs with low levels of lipid induced regulatory T cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DCs required their secretion of tumor necrosis factor α and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity. CONCLUSIONS: Human and mouse hepatic DCs are composed of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver.

Diabetic and bariatric surgery: a review of the recent trends.

INTRODUCTION: Bariatric surgery is currently the most effective treatment for diabetes associated with morbid obesity. METHODS: A Pubmed search was made for all articles on bariatric surgery and diabetes from 2009 to present (March 2011) in order to identify the recent advances in this field. Herein we review the recent data available on the long-term effects of bariatric surgery on diabetes. We also review the efficacy of gastrointestinal surgery done for diabetic patients having body mass index (BMI) <35 kg/m(2) and also the effect of novel bariatric procedures on diabetes associated with obesity. Finally, the efficacy of bariatric surgery in adolescent diabetes and the recent epidemiological trends of type 2 diabetes are also dealt with briefly. CONCLUSION: RYGB and biliopancreatic diversion (BPD) are effective surgical options for diabetes in the long term (>5 yrs). The efficacy of sleeve gastrectomy on diabetes in the long term is not yet known. Gastrointestinal procedures for non morbidly obese and non obese patients have shown great promise as surgical optional for diabetes, though their efficacy and safety in the long term are unknown. Novel endoscopic techniques and TANTALUS have shown some promise in resolving diabetes in obese patients. Bariatric surgery is very effective is resolving adolescent diabetes.

Progressive Non-familial Adult onset Cerebellar Degeneration: An Unusual Occurrence with Hashimoto's Thyroiditis.

Progressive non-familial adult onset cerebellar degeneration has been rarely associated with hypothyroidism and is known to be reversible after therapy. We report a case of cerebellar atrophy in a 31 year old female whose detailed evaluation had revealed sub-clinical hypothyroidism secondary to autoimmune thyroiditis with a very high anti-TPO (anti-thyroid peroxidase) antibody levels. MRI (Magnetic Resonanace Imaging) of brain showed diffuse bilateral cerebellar atrophy. She was treated with thyroid hormone supplementation and after one year of follow up, cerebellar signs had disappeared completely with significant reduction in anti-TPO antibody levels. Imaging of the brain post one year of follow-up revealed normal cerebellum. Hence, we opine that thyroid dysfunction should always be kept in mind while evaluating patients presenting with acute onset cerebellar ataxia as it can be easily reversed with thyroid hormone replacement therapy.

Bariatric surgery and the central nervous system.

Bariatric procedures are now known to have an effect on hunger as well as on metabolism. The role of central nervous pathways in causing these effects after bariatric surgery is now being elucidated. A brief overview of these pathways has been presented for the sake of bariatric surgeons. A PubMed search was made using various search phrases to retrieve all original articles concerning the effect of bariatric surgery on the neural pathways. The mechanisms regulating the food intake and energy expenditure can be broadly divided into homeostatic and hedonic systems. The effect of bariatric surgery on the homeostatic system in animal models is not clear. A decrease in preference for sweet taste and high calorie foods has been demonstrated in animal models. The effect of bariatric surgery on the hedonic system in humans has been consistent with decreased activation of the hedonic system being demonstrated by functional MRI and decreased preference for intake of high energy foods also being observed post-surgery. The effect of bariatric surgery on dopamine signaling, which is involved in the hedonic system, is however not clear. Functional MRI studies have also demonstrated increased activation of the hypothalamus after surgery. Various studies utilizing questionnaires have demonstrated increased satiety and decreased hunger after bariatric surgery.

GIP and bariatric surgery.

Bariatric surgery is the most effective modality of achieving weight loss as well as the most effective treatment for type 2 diabetes mellitus (T2DM). Glucose-dependent insulinotropic polypeptide (GIP) is an incretin and is implicated in the pathogenesis of obesity and T2DM. Its role in weight loss and resolution of T2DM after bariatric surgery is very controversial. We have made an attempt to review the physiology of GIP and its role in weight loss and resolution of T2DM after bariatric surgery. We searched PubMed and included all relevant original articles (both human and animal) in the review. Whereas most human studies have shown a decrease in GIP post-malabsorptive bariatric surgery, the role of GIP in bariatric surgery done in animal experiments remains inconclusive.

Animal models in bariatric surgery--a review of the surgical techniques and postsurgical physiology.

Bariatric surgery is considered the most effective current treatment for morbid obesity. Since the first publication of an article by Kremen, Linner, and Nelson, many experiments have been performed using animal models. The initial experiments used only malabsorptive procedures like intestinal bypass which have largely been abandoned now. These experimental models have been used to assess feasibility and safety as well as to refine techniques particular to each procedure. We will discuss the surgical techniques and the postsurgical physiology of the four major current bariatric procedures (namely, Roux-en-Y gastric bypass, gastric banding, sleeve gastrectomy, and biliopancreatic diversion). We have also reviewed the anatomy and physiology of animal models. We have reviewed the literature and presented it such that it would be a reference to an investigator interested in animal experiments in bariatric surgery. Experimental animal models are further divided into two categories: large mammals that include dogs, cats, rabbits, and pig and small mammals that include rats and mice.