Atherosclerosis and metabolic disease

Cholesterol plays an important role in atherogenesis. Cholesterol-ester that has been carried by circulating low-density lipoprotein particles accumulates in the atherosclerotic plaque. Statins are considered the most potent and effective agents for reducing low-density lipoprotein cholesterol and the incidence of cardiovascular events. Total cholesterol and LDL cholesterol levels, however, are not always a useful marker for distinguishing patients with or without cardiovascular disease. Low levels of high-density lipoprotein cholesterol are the most predictive marker for cardiovascular disease. Low HDL cholesterol levels originate in some genetic and acquired diseases and conditions. Most cases of low HDL cholesterol associated with the development of atherosclerosis are of secondary origin, especially those associated with increasing triglyceride-rich lipoprotein. These conditions are present in insulin-resistant syndrome, namely metabolic syndrome. Type 2 diabetes mellitus and the closely related metabolic syndrome are associated with a significant risk for cardiovascular disease. Recent evidence suggests that both conditions are increasing in epidemic proportions. Dyslipidemia is characterized by increased triglyceride-rich lipoproteins; low high-density lipoprotein cholesterol; small, dense low-density lipoprotein particles; and increased postprandial lipemia. All these lipoprotein disturbances accelerate atherosclerosis. It is likely that many patients will need lipid-modifying therapy to help prevent cardiovascular disease.     

Vascular and metabolic reserve in Alzheimer's disease

Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.     

Early life programming of obesity and metabolic disease

It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.     

NLRP3 inflammasomes link inflammation and metabolic disease

A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here, we review these new developments and discuss their implications for a better understanding of inflammation in metabolic disease, and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.     

Cell-based therapies for metabolic liver disease

Liver transplantation is an important therapeutic option for many individuals with metabolic liver disease. Nevertheless, the invasive nature of surgery and limitations of donor organ availability have led to the search for alternatives to whole-organ transplantation. Cell-based therapies have been a particularly active area of investigation in recent years. Hepatocyte transplantations have been performed for a variety of indications, including acute liver failure, end-stage liver disease, and inborn errors of metabolism. Individuals with inborn errors of metabolism who have undergone hepatocyte transplantation have shown clinical improvement and partial correction of the underlying metabolic defect. In most cases, sustained benefits have not been observed. This may be related to inadequate cell dose, variations in the quality of hepatocyte preparations, rejection of the transplanted cells, or senescence of transplanted hepatocytes. Though initial proof of concept with hepatocyte transplantation has been demonstrated by a number of investigators, wide application of this technology has been hindered by the inability to secure a reliable and well-characterized cell source(s) for transplantation and by the challenges of sustained engraftment and expansion of transplanted cells in vivo. Cell-based therapies, including those based on stem cells or more differentiated progenitor cells, may represent the future of cell transplantation for treatment of metabolic liver disease.     

Liver transplantation for pediatric metabolic disease

Liver transplantation (LTx) was initially developed as a therapy for liver diseases known to be associated with a high risk of near-term mortality but is based upon a different set of paradigms for inborn metabolic diseases. As overall outcomes for the procedure have improved, LTx has evolved into an attractive approach for a growing number of metabolic diseases in a variety of clinical situations. No longer simply life-saving, the procedure can lead to a better quality of life even if not all symptoms of the primary disorder are eliminated. Juggling the risk-benefit ratio thus has become more complicated as the list of potential disorders amenable to treatment with LTx has increased. This review summarizes presentations from a recent conference on metabolic liver transplantation held at the Children's Hospital of Pittsburgh of UPMC on the role of liver or hepatocyte transplantation in the treatment of metabolic liver disease.     

The histology of metabolic bone disease

Patients with metabolic bone disease are usually cared for by endocrinologists. Pathologists may examine specimens if fragility fractures occur or if a bone biopsy is required. Some metabolic bone diseases have distinctive histologic features such as tunneling resorption in hyperparathyroidism, wide osteoid seams in osteomalacia, and bone marrow edema in transient osteoporosis. The histologic changes must always be correlated with clinical and radiographic features.     

Histopathologic changes in metabolic bone disease

Metabolic bone disease encompasses a heterogeneous group of disorders that influence skeletal metabolism and structure. They are generally diagnosed at an advanced stage and manifest clinically with stunted skeletal growth in children and pathologic fractures in adults. Biochemical markers for bone metabolism are equivocal and microscopic examination of labeled bone remains the gold standard for the diagnosis and accurate monitoring of the response to therapy. This article reviews the role of microscopic bone changes in the diagnosis and management of metabolic bone disease.     

Immunomodulation at epithelial sites by obesity and metabolic disease

Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options.     

Maternal obesity, metabolic disease, and allostatic load

Maternal obesity is a risk factor for many metabolic diseases for the mother, both during gestation and post partum, and for the child in later life. Obesity and pregnancy both result in altered physiological states, significantly different from the state of the non-obese, non-reproductive adult female. The concept of allostasis may be more appropriate for understanding the physiology of both pregnancy and obesity. In pregnancy these altered physiological states are adaptive, in both the evolutionary and physiological senses of the word. Obesity, however, represents a state outside of the adaptive evolutionary experience of our species. In both cases the altered physiological state derives at least in part from signals from an active endocrine organ. In obesity this is adipose tissue, and in pregnancy it is the placenta. The signaling molecules from adipose tissue and placenta all have multiple functions and can affect multiple organ systems. Placenta acts as a central regulator of metabolism for both the maternal and fetal compartments, in essence acting as a "third brain" during pregnancy. Both adipose tissue and placenta express many proinflammatory cytokines; obesity and pregnancy are states of low-grade inflammation. Both obesity and pregnancy are also states of insulin resistance, and maternal obesity is associated with fetal insulin resistance. We argue that obesity during pregnancy leads to sustained and inappropriate activation of normally adaptive regulatory circuits due in part to competing and conflicting signaling from adipose tissue and placenta. This results in allostatic load, leading to the eventual break down of regulatory mechanisms. The result is impaired metabolic function of the mother, and altered development of metabolic systems and potentially altered neural appetite circuits for the offspring.     

Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease

The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin–angiotensin–aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.     

非酒精性脂肪性肝病与代谢综合征的关系研究

目的:探讨非酒精性脂肪性肝病患病与代谢综合征的关系。方法:采用横断面调查研究方法,分析810例健康体检者的体重指数、血压、总胆固醇、甘油三酯、空腹血糖和肝脏超声检查相关临床资料。结果:非酒精性脂肪性肝病组中体重指数、血压、总胆固醇、甘油三酯和空腹血糖水平均明显高于对照组(P0.01);多因素Logistic回归分析结果显示,代谢综合征各组分中体重指数、甘油三酯、空腹血糖及舒张压升高是非酒精性脂肪性肝病发病的独立危险因子(P0.05)。结论:非酒精性脂肪性肝病患病与代谢综合征密切相关。