xin Li

Lecithin Cholesterol Acyltransferase Null Mice Are Protected from Diet-induced Obesity and Insulin Resistance in a Gender-specific Manner through Multiple Pathways

Complete lecithin cholesterol acyltransferase (LCAT) deficiency uniformly results in a profound HDL deficiency. We recently reported unexpected enhanced insulin sensitivity in LCAT knock-out mice in the LDL receptor knock-out background (Ldlr−/−×Lcat−/−; double knock-out (DKO)), when compared with their Ldlr−/−×Lcat+/+ (single knock-out (SKO)) controls. Here, we report that LCAT-deficient mice (DKO and Lcat−/−) are protected against high fat high sucrose (HFHS) diet-induced obesity without hypophagia in a gender-specific manner compared with their respective (SKO and WT) controls. The metabolic phenotypes are more pronounced in the females. Changes in endoplasmic reticulum stress were examined as a possible mechanism for the metabolic protection. The female DKO mice developed attenuated HFHS-induced endoplasmic reticulum stress as evidenced by a lack of increase in mRNA levels of the hepatic unfolded protein response (UPR) markers Grp78 and CHOP compared with SKO controls. The DKO female mice were also protected against diet-induced insulin resistance. In white adipose tissue of chow-fed DKO mice, we also observed a reduction in UPR, gene markers for adipogenesis, and markers for activation of Wnt signaling. In skeletal muscles of female DKO mice, we observed an unexpected increase in UCP1 in association with increase in phospho-AMPKα, PGC1α, and UCP3 expressions. This increase in UCP1 was associated with ectopic islands of brown adipocytes between skeletal muscle fibers. Our findings suggest that LCAT deficiency confers gender-specific protection against diet-induced obesity and insulin resistance at least in part through regulation in UPR, white adipose tissue adipogenesis, and brown adipocyte partitioning.

Lecithin:Cholesterol Acyltransferase Deficiency Protects against Cholesterol-induced Hepatic Endoplasmic Reticulum Stress in Mice

Background: Hepatic ER stress promotes insulin resistance, but the role of cholesterol in this pathway is unknown. Results: LCAT-deficient mice maintain a low ER cholesterol and are protected from cholesterol-induced ER stress. Conclusion: ER cholesterol, not tissue cholesterol, is crucial for hepatic ER stress development. Significance: Modulators of hepatic ER cholesterol may be novel targets to treat diabetes. We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr−/−xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr−/−xLcat−/− mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr−/−xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr−/−xLcat−/− mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr−/−xLcat−/− mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr−/−xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr−/−xLcat−/− mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.

Insulin modulates ischemia-induced endothelial progenitor cell mobilization and neovascularization in diabetic mice

Decreased levels of circulating endothelial progenitor cells (EPCs) predict increased risk of cardiovascular events in diabetic patients. Insulin treatment exerts important cardiovascular protection. Whether and how insulin participates in the EPC regulation of postnatal neovascularization are currently unclear. We employed a mouse hindlimb ischemia model to study EPC mobilization in non-diabetic and streptozotocin-induced diabetic mice. Insulin was administered to diabetic animals postoperatively. To determine the role of EPCs contributing to postnatal vasculogenesis, we used bone marrow-transplanted mice whose bone marrow cells selectively expressed enhanced green fluorescent protein (EGFP). Insulin treatment improved EPC mobilization into peripheral blood, accelerated transcutaneous oxygen pressure restoration and increased capillary density in the ischemic limb associated with partial incorporation of EGFP-positive cells into the capillaries. Insulin treatment restored ischemia-induced release of stromal-derived growth factor 1α and vascular endothelial growth factor (VEGF), and consequently enhanced the activity of Akt and endothelial nitric oxide synthase (eNOS) as well as matrix metalloproteinase-9 in bone marrow. Insulin also augmented tissue-level activation of VEGF/Akt/eNOS pathway. However, all such effects of insulin were completely blocked by combined treatment with a NOS inhibitor. Our data suggested that insulin treatment improved ischemia-induced EPC mobilization and contributed to compensatory neovascularization in diabetic mice through a VEGF/eNOS-related pathway.

Hashimoto encephalopathy: literature review.

Hashimoto encephalopathy (HE) presents as an encephalopathy without central nervous system infection or tumor. HE is associated with autoimmune thyroiditis and is thus considered to be an autoimmune disorder. The prevalence of HE is low, but death and status epilepticus have been reported. HE manifests with a wide range of symptoms that include behavioral changes and confusion. Elevated thyroid antibodies are present in the majority of cases and are required for the diagnosis of HE. Normal brain MRI findings are found in the majority of patients diagnosed with HE. The most consistent CSF abnormality noted in HE patients is the presence of elevated protein. Most HE patients respond well to steroid therapy. Clinical improvements are also observed with IV immunoglobulin and plasmapheresis. In conclusion, it is now generally accepted that the diagnosis of HE must include encephalopathy characterized by cognitive impairment associated with psychiatric features, such as hallucinations, delusions, and paranoia. Autoimmune encephalitis and prion disease should be considered in the differential diagnosis due to the similarity of the clinical features of these conditions to those of HE.

A New Role for an Old Drug: Metformin Targets MicroRNAs in Treating Diabetes and Cancer.

Preclinical Research

MicroRNAs are key regulators of brown adipogenesis.

The recent discovery of microRNA, thousands of short, non-coding strands of RNA that regulate gene expressions on the transcriptional level throughout the body, raises the possibility of their roles as therapeutic targets in the treatment of a diverse range of diseases including diabetes, cancer, cardiovascular disease, and obesity. Specifically, their potential as therapeutic targets in the treatment of obesity has been highlighted. Brown adipose tissue containing a large number of mitochondria and expressing Ucp-1 is metabolically active through dissipating energy as heat in cold temperatures. Brown adipose, which was previously thought to be present only in neonatal and infants, has been recently unexpectedly identified in various anatomical regions of the adult human body. Furthermore, brown adipocytes have been shown to originate from skeletal and cardiovascular myoblast progenitor cells. Several identified microRNAs participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-β program. These miRNAs are potential therapeutic targets in the induction of brown adipocyte lineage differentiation from myoblast and white adipose, through which the Ucp-1 expression is regulated to increase calorie expenditure and reduce body weight in obese individuals. This review focuses on the current understanding of miRNAs on the regulation of brown adipogenesis.

Emerging role of cellular cholesterol in the pathogenesis of nonalcoholic fatty liver disease.

This section provides a rapid update service, covering the whole field of lipidology, and lists papers entered into the publisher’s database from OvidSP. Key articles are selected for comment by specialists and are highlighted in the following way: Papers considered to be of specialist interest Papers considered to be of outstanding interest A bibliographic listing follows each comment and selected papers are accompanied by an annotation in which the scope and context of the article are summarized briefly. Current Opinion in Lipidology 2013, 24:274–281 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0957-9672

Sleep duration and smoking are associated with coronary heart disease among US adults with type 2 diabetes: Gender differences

AIMS The associations of moderate alcohol consumption, sleep duration, and tobacco smoking with coronary heart disease (CHD) among patients with type 2 diabetes mellitus (T2D) are not clearly clarified. The aims of the study were to evaluate the associations of lifestyle factors, hypertension, obesity, depression and sleep duration with CHD development among patients with T2D, and particularly, to examine the gender differences in risk factors for CHD. METHODS A total of 2335 T2D adults were selected from the 2012 National Health Interview Survey. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios with 95% confidence intervals. RESULTS The CHD prevalence among patients with T2D was 14.2% (18.1% and 10.4% for males and females, respectively), which increased with age (10.3% and 19.6% for age groups 18-64 and 65+, respectively). After adjusting for other factors, weighted logistic regression analyses showed that CHD among patients with T2D was significantly associated with being male, older age, past smoking, long sleep duration, hypertension, and high cholesterol level. Furthermore, the significant association of older age, past smoking, hypertension and high cholesterol level were observed particularly in males, while the association of long sleep duration with CHD was only observed in females. Hypertension was associated with CHD for both genders. CONCLUSIONS Gender, age, past smoking, long sleep duration, hypertension and high cholesterol level were significantly associated with CHD among T2D patients; however, such associations differed by gender. Such gender disparities should be considered in the prevention and treatment of T2D.

Integrating Medical Simulation Into the Physician Assistant Physiology Curriculum.

Purpose Medical simulation has recently been used in medical education, and evidence indicates that it is a valuable tool for teaching and evaluation. Very few studies have evaluated the integration of medical simulation in medical physiology education, particularly in PA programs. This study was designed to assess the value of integrating medical simulation into the PA physiology curriculum. Methods Seventy-five students from the PA program at Central Michigan University participated in this study. Mannequin-based simulation was used to simulate a patient with hemorrhagic shock and congestive heart failure to demonstrate the Frank–Starling force and cardiac function curve. Before and after the medical simulation, students completed a questionnaire as a self-assessment. A knowledge test was also delivered after the simulation. Results Our study demonstrated a significant improvement in student confidence in understanding congestive heart failure, hemorrhagic shock, and the Frank–Starling curve after the simulation. Conclusions Medical simulation may be an effective way to enhance basic science learning experiences for students and an ideal supplement to traditional, lecture-based teaching in PA education.

Metformin: An Old Drug with New Applications

Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action.