Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia.

Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p ˂ 0.05) and decreased CYP4A (p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p ˂ 0.01), lipogenesis (p ˂ 0.05) and lipolysis (p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.

Repercussões metabólicas: quais, como e por que investigar? / Metabolic repercussions: which ones, how and why investigate?

A síndrome dos ovários policísticos (SOP) é frequentemente acompanhada de distúrbio metabólico, principalmente dos carboidratos e dos lipídeos, aumentando o risco de síndrome metabólica. Por essa razão, alguns investigadores ainda denominam a SOP de síndrome metabólica-reprodutiva. O objetivo deste capítulo é descrever as principais repercussões metabólicas, bem como como investigá-las e saber como suas consequências podem ser deletérias para a saúde da mulher. Esta é uma revisão narrativa mostrando a implicação do metabolismo dos carboidratos e dos lipídeos nas dislipidemias, bem como da síndrome metabólica sobre o sistema reprodutor, e o risco cardiovascular da mulher com SOP. Conclui-se que o manejo adequado dos distúrbios metabólicos na SOP é benéfico a curto e a longo prazo tanto para o sistema reprodutor quanto para o cardiovascular.(AU)

Lipid disorders in children living with overweight and obesity- large cohort study from Poland.

BACKGROUND: While in the general paediatric population the presence of abnormal lipid values is estimated at 8-20%, depending on the population, accepted norms and age, it was shown that in the population of lean children the prevalence of dyslipidemia is lower than in obese children, in whom it ranges from 20 to over 40%. Until now, however, no results of similar studies on a large sample of children form a Central or Eastern European country have been published. The aim of this study was to evaluate the prevalence of lipid disorders in overweight and obese children and adolescents participating in an integrated weight reduction programme. METHODS: According to the "6-10-14 for Health" programme implementation schedule, the programme accepted patients living in Gdansk, aged 6, 9-11 and 14 years old, with BMI above the 85th percentile for age and sex, according to the Polish percentile charts. During the first visit, each of the participants underwent basic anthropometric examinations - body weight, body height, waist and hip circumference, blood pressure and body composition by bioelectrical impedance were measured. Blood samples were taken to assess lipid, glucose and insulin levels as well as alanine transaminase (ALT) and thyroid stimulating hormone (TSH) activity. RESULTS: 1948 patients underwent full anthropomethric and blood work measurements. At least one of the lipid disorders occurred in 38.23% of girls and 40.51% of boys with overweight and obesity. The most common lipid disorderswere decreased high-density lipoprotein cholesterol (HDL-C) levels (present in 20.55% of the girls and 23.79% of the boys) and elevated low-density lipoprotein cholesterol (LDL-C) (present in 15.31% of the girls and 14.25% of the boys). There was no strong association between lipid disorders and age, sex, birth weight, gestational age at birth or body composition. CONCLUSIONS: Such a frequent occurrence of lipid disorders in the population of children and adolescents should be an important warning signal both at the individual and population level. Not only effective screening methods for overweight and obese children should be implemented from an early age but also therapeutic measures are required. TRIAL REGISTRATION: The trial is registered under the Local Ethics Committee at Medical University of Gdansk, decision No. NKBBN/228/2012 from 25 June 2012.

Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.

Menopause is clinically diagnosed as a condition when a woman has not menstruated for one year. During the menopausal transition period, there is an emergence of various lipid metabolic disorders due to hormonal changes, such as decreased levels of estrogens and increased levels of circulating androgens; these may lead to the development of metabolic syndromes including cardiovascular diseases and type 2 diabetes. Dysregulation of lipid metabolism affects the body fat mass, fat-free mass, fatty acid metabolism, and various aspects of energy metabolism, such as basal metabolic ratio, adiposity, and obesity. Moreover, menopause is also associated with alterations in the levels of various lipids circulating in the blood, such as lipoproteins, apolipoproteins, low-density lipoproteins (LDLs), high-density lipoproteins (HDL) and triacylglycerol (TG). Alterations in lipid metabolism and excessive adipose tissue play a key role in the synthesis of excess fatty acids, adipocytokines, proinflammatory cytokines, and reactive oxygen species, which cause lipid peroxidation and result in the development of insulin resistance, abdominal adiposity, and dyslipidemia. This review discusses dietary recommendations and beneficial compounds, such as vitamin D, omega-3 fatty acids, antioxidants, phytochemicals-and their food sources-to aid the management of abnormal lipid metabolism in postmenopausal women.

Mitochondrial and Metabolic Myopathies.

PURPOSE OF REVIEW: This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination. RECENT FINDINGS: Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies. SUMMARY: Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.

Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease.

PURPOSE OF REVIEW: The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. RECENT FINDINGS: Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.

Nonalcoholic Fatty Pancreas Disease.

Nonalcoholic fatty pancreas disease (NAFPD) describes a phenotype of pancreatic steatosis (PS) that is not caused by alcohol consumption, viral infections, toxins, or congenital metabolic syndromes but is associated with insulin resistance, malnutrition, obesity, metabolic syndrome, or increasing age. NAFPD is a relatively new disease entity, as the clinical significance of fatty infiltration of pancreas has gained attention recently. Clinical consequences of NAFPD remain largely unknown despite clinical associations. This review aims to study similarities and differences between hepatic and PS and explore recent advances in NAFPD.

Lipid Metabolism Disorder and Renal Fibrosis.

Since the lipid nephrotoxicity hypothesis was proposed in 1982, increasing evidence has supported the hypothesis that lipid abnormalities contributed to the progression of glomerulosclerosis. In this chapter, we will discuss the general promises of the original hypothesis, focusing especially on the role of lipids and metabolic inflammation accompanying CKD in renal fibrosis and potential new strategies of prevention.

Pancreatic steatosis: an update.

PURPOSE OF REVIEW: Pancreatic steatosis is a clinical entity with emerging significance and impacts patient health in a multitude of ways. It has a high prevalence in the global population with predilections for different demographics by age, sex and ethnicity. Understanding the pathophysiology, clinical features and complications of this entity may be important to understanding the consequences of the ongoing obesity global epidemic. RECENT FINDINGS: Obesity and metabolic syndrome contribute to metabolic derangements that result in lipid mishandling by adipocytes. Adipocytokine imbalances in circulation and in the pancreatic microenvironment cause chronic, low-grade inflammation. The resulting beta cell and acinar cell apoptosis leads to pancreatic endocrine and exocrine dysfunction. Furthermore, these adipocytokines regulate cell growth, differentiation, as well as angiogenesis and lymphatic spread. These consequences of adipocyte infiltration are thought to initiate carcinogenesis, leading to pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. SUMMARY: Obesity will lead to millions of deaths each year and pancreatic steatosis may be the key intermediate entity that leads to obesity-related complications. Enhancing our understanding may reveal strategies for preventing mortality and morbidity related to the global epidemic of obesity. Further research is needed to determine the pathophysiology, long-term complications and effective treatment strategies for this condition.

Molecular mechanisms of lipid metabolism disorder in livers of ewes with pregnancy toxemia.

Pathogenesis of pregnancy toxemia (PT) is believed to be associated with the disruption of lipid metabolism. The present study aimed to explore the underlying mechanisms of lipid metabolism disorder in the livers of ewes with PT. In total, 10 pregnant ewes were fed normally (control group) whereas another 10 were subjected to 70% level feed restriction for 15 days to establish a pathological model of PT. Results showed that, as compared with the controls, the levels of blood ß-hydroxybutyrate (BHBA), non-esterified fatty acids (NEFAs) and cholesterol were greater (P<0.05) and blood glucose level was lower (P<0.05) in PT ewes. The contents of NEFAs, BHBA, cholesterol and triglyceride were higher (P<0.05) and glycerol content was lower (P<0.05) in hepatic tissues of PT ewes than those of the controls. For ewes with PT, excessive fat vacuoles were observed in liver sections stained with hematoxylin-eosin; furthermore, inner structures of hepatocytes including nuclei, mitochondria and endoplasmic reticulum were damaged seriously according to the results of transmission electron microscope. Real-time PCR data showed that compared with the controls, the expression of hepatic genes involved in fatty acid oxidation (FAO) and triglyceride synthesis (TGS) was enhanced (P<0.05) whereas that related to acetyl-CoA metabolism (ACM) was repressed (P<0.05) in PT ewes. Generally, our results showed that negative energy balance altered the expression of genes involved in FAO, ACM and TGS, further caused lipid metabolism disorder in livers, resulting in PT of ewes. Our findings may provide the molecular basis for novel therapeutic strategies against this systemic metabolic disease in sheep.

Role of coagulopathy in glucocorticoid-induced osteonecrosis of the femoral head.

The two major theories of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) are apoptosis and ischaemia. The traditional theory implicates ischaemia as the main aetiological factor because the final common pathway of ONFH is interruption of blood supply to the bone. The most common causes of interruption of blood supply include fat embolism and coagulation disorders. GCs can directly or indirectly lead to coagulation disorders, producing a hypercoagulable state, followed by poor blood flow, ischaemia, and eventually ONFH. This review summarizes the existing knowledge on coagulation disorders in the context of GC-induced ONFH, including hypofibrinolysis and thrombophilia, endothelial cell dysfunction and damage, endothelial cell apoptosis, lipid metabolism, platelet activation, and the effect of anticoagulant treatment.

Assessment of intestinal malabsorption.

Significant efforts have been made in the last decade to either standardize the available tests for intestinal malabsorption or to develop new, more simple and reliable techniques. The quest is still on and, unfortunately, clinical practice has not dramatically changed. The investigation of intestinal malabsorption is directed by the patient's history and baseline tests. Endoscopy and small bowel biopsies play a major role although non-invasive tests are favored and often performed early on the diagnostic algorithm, especially in paediatric and fragile elderly patients. The current clinically available methods and research tools are summarized in this review article.

GASTROESOPHAGEAL REFLUX DISEASE IN ASSOCIATION WITH LIPID-METABOLIC INDICATORS AT THE YAKUTSK.

AIM: To estimate interrelations of gastroesophageal reflux disease with lipid-metabolic indicators at the Yakutsk. MATERIALS AND METHODS: A one-stage investigation of 100 patients of the Yakut nationality with gastroesophageal reflux disease (GERD) is carried out. For estimating the association of GERD clinical symptoms with lipid-metabolic indicators a method of binary logistical regress with compulsory inclusion of predictors has been used. RESULTS: According to results of the comparison most statistically significant distinctions of metabolic indicators are revealed at GERD esophageal (eructation) and extra-esophageal symptoms (night cough), dyspepsia (distention, epigastric heaviness), as well as snoring. Logistical regression analysis has confirmed interrelation of clinical symptoms with lipid-metabolic indicators, as waist circumference, a level of arterial pressure and blood lipid (triglycerides, lipoprotein cholesterol of low and high density). CONCLUSIONS: Thus, the estimation of interrelation of GERD clinical symptoms with MS criteria at the Yakutsk has revealed the influence of MS components, especially abdominal adiposity, arterial hypertension and triglycerides on the development of dyspepsic symptoms (distention, epigastric heaviness), GERD esophageal (eructation) and extra-esophageal manifestations (night cough).

Impact of N-acetylcysteine and etodolac treatment on systolic and diastolic function in a rat model of myocardial steatosis induced by high-fat-diet.

OBJECTIVES: Obesity is a worldwide problem, leading to cardiomyopathy. Oxidative stress and inflammation have been reported to play significant roles in developing obesity cardiomyopathy. N-acetylcysteine is a glutathione prodrug that preserves liver against steatosis via constraining the production of reactive oxygen species. Etodolac is a nonsteroidal anti-inflammatory drug which has been demonstrated to protect liver against fibrosis. The aim of the present study was to evaluate and compare the effects of N-acetylcysteine and etodolac on impaired cardiac functions due to high-fat-diet (HFD) induced myocardial steatosis in rats. MATERIAL AND METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Control group was maintained on standard-rat-basic-diet (SD) for 20 weeks, while HFD was given to three study groups for 20 weeks. Then N-acetylcysteine was given to one of the study groups (HFD+NAC), and etodolac to another group (HFD+ETD) as a supplement for 4 weeks while all groups were continued on SD. At the end of the study periods, hearts were examined by Langendorff technique and rat livers were evaluated histologically. RESULTS: HFD and HFD+ETD groups presented with significantly higher steatosis and fibrosis in liver compared to other groups. HFD+NAC preserved diastolic functions. Also HFD+NAC and HFD+ETD groups had significantly better systolic funtions than HFD group. CONCLUSIONS: Obesity is associated with diastolic dysfunction rather than systolic dysfunction. NAC may protect the heart against diastolic dysfunction due to obesity. NAC and etodolac treatment improve systolic function, even in the absence of systolic dysfunction.

JCL Roundtable: enzyme replacement therapy for lipid storage disorders.

There are several inherited disorders that involve abnormal storage of lipids in tissues leading to severe compromise of organs. Sadly, these are often accompanied by lifelong morbidity and early mortality. Disorders such as Gaucher, Fabry, and lysosomal acid lipase deficiencies (Wolman and cholesteryl ester storage diseases) have been known for many years, and provide a difficult and frustrating set of problems for patients, their families, and their physicians. With recombinant methods of protein synthesis, it is now possible to literally replace the defective enzymes that underlie the basic pathophysiology of many such disorders. The delivery of these enzymes into the affected cells is possible because of their location in the lysosomes where the natural degradation of their lipid substrates occurs. I have asked 2 well-known investigators to join us for this Roundtable. These are professors who have been involved with the research that has made this type of therapy possible and who have participated in the clinical trials that demonstrated the value of enzyme replacement therapy. They are Dr. Robert Desnick, dean of Genetic and Genomic Medicine and professor and chairman emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and Dr. Gregory Grabowski, professor of Microbiology, Biochemistry, and Pediatrics, at the University of Cincinnati College of Medicine. Dr. Grabowski recently retired from that school to become the chief science officer of Synageva, a company involved in producing enzymes for this type of therapy.

[Long-term effects of mild hyperglycemia exposure in utero and postnatal high fat diet on body weight and lipid metabolism in rat offsprings].

OBJECTIVE: To investigate the long-term effects of intrauterine mild hyperglycemia exposure and postnatal high fat diet on the body weight and metabolism of offspring through a pregnant rat model of intrauterine mild hyperglycemia. METHODS: Twenty-one pregnant Wistar rats were randomly divided into intrauterine hyperglycemia group and control group. Twenty percent streptozotocin (STZ, 25 mg/kg)was given to rats of intrauterine hyperglycemia group by a single intraperitoneal injection to induce intrauterine mild hyperglycemia; control group rats received an equal volume of citric acid-sodium citrate buffer. Off springs were divided into 4 groups: exposed to intrauterine hyperglycemia and fed with normal diet group (group DN) or high fat diet group (group DF); exposed to intrauterine euglycemia and fed with normal diet group (group CN) or high fat diet group (group CF). The blood glucose levels of pregnant rats in two groups and body weights of offsprings in four groups were recorded. At the age of 28 weeks, the mesenteric fat amount, epididymal amount, perirenal fat amount, total triglyceride (TG) and high density 1ipoprotein-cholestrol (HDL-C) were measured in all four groups. RESULTS: (1)The average blood glucose level of intrauterine hyperglycemia group [(16.6 ± 3.4) mmol/L] was significantly higher than that of the control group [(5.8 ± 1.1) mmol/L, P < 0.01]. (2) On the birth day, 3 weeks and 4 weeks, the body weight of group DN[(7.4 ± 0.6), (44.1 ± 5.9), (79.6 ± 7.4) g] and group DF [(7.4 ± 0.2), (43.9 ± 6.9), (76.1 ± 5.8) g] were remarkably increased compared with group CN [(6.6 ± 0.5),(35.6 ± 4.4),(71.5 ± 6.8) g, P < 0.05]; but the body weight in group CF [(6.7 ± 0.5),(33.0 ± 6.5),(66.1 ± 10.2) g] had no statistical difference compared with group CN (P > 0.05). (3)From then on, the body weights of the offsprings in four groups presented an increasing trend, but there was no statistical difference until 28 weeks (P > 0.05). (4) The perirenal fat amount of group DN, group CF and group DF [(13.8 ± 3.3), (14.3 ± 3.2), (18.4 ± 1.3) g] were remarkably increased compared with group CN[(9.7 ± 3.5) g, P < 0.05]; the epididymal fat amount of group CF and group DF were also significantly increased compared to group CN (P < 0.05); the mesenteric fat amount in four groups had no statistical difference (P > 0.05). (5) The TG level of group DN, group CF and group DF [(0.52 ± 0.14), (0.52 ± 0.09), (0.54 ± 0.17) mmol/L] were significantly higher compared to group CN [(0.41 ± 0.09) mmol/L, P < 0.05], but there was no statistical difference within the first three groups (P > 0.05); the HDL-C level in four groups had no statistical difference (P > 0.05). CONCLUSIONS: In intrauterine mild hyperglycemia environment, there were some evidently metabolic changes observed in the offspring, including body weight increasing on birth day and early postnatal period, visceral fat amount increasing and lipid metabolism disorders, which could be aggravated by postnatal high fat diet.

Relationship between resting pulse rate and lipid metabolic dysfunctions in Chinese adults living in rural areas.

BACKGROUND: Resting pulse rate has been observed to be associated with cardiovascular diseases. However, its association with lipid metabolic dysfunctions remains unclear, especially resting pulse rate as an indicator for identifying the risk of lipid metabolic dysfunctions. The purpose of this study was to examine the association between resting pulse rate and lipid metabolic dysfunctions, and then evaluate the feasibility of resting pulse rate as an indicator for screening the risk of lipid metabolic dysfunctions. METHODS: A cross-sectional survey was performed, and 16,926 subjects were included in this study from rural community residents aged 35-78 years. Resting pulse rate and relevant covariates were collected from a standard questionnaire. The fasting blood samples were collected and measured for lipid profile. Predictive performance was analyzed by receiver operating characteristic (ROC) curve. RESULTS: A significant correlation was observed between resting pulse rate and TC (r = 0.102, P = 0.001), TG (r = 0.182, P = 0.001), and dyslipidemia (r = 0.037, P = 0.008). In the multivariate models, the adjusted odds ratios for hypercholesterolemia (from 1.07 to 1.15), hypertriglyceridemia (1.11 to 1.16), low HDL hypercholesterolemia (1.03 to 1.06), high LDL hypercholesterolemia (0.92 to 1.14), and dyslipidemia (1.04 to 1.07) were positively increased across quartiles of resting pulse rate (P for trend <0.05). The ROC curve indicated that resting pulse rate had low sensitivity (78.95%, 74.18%, 51.54%, 44.39%, and 54.22%), specificity (55.88%, 59.46%, 57.27%, 65.02%, and 60.56%), and the area under ROC curve (0.70, 0.69, 0.54, 0.56, and 0.58) for identifying the risk of hypercholesterolemia, hypertriglyceridemia, low HDL hypercholesterolemia, high LDL hypercholesterolemia, and dyslipidemia, respectively. CONCLUSION: Fast resting pulse rate was associated with a moderate increased risk of lipid metabolic dysfunctions in rural adults. However, resting pulse rate as an indicator has limited potential for screening the risk of lipid metabolic dysfunctions.

Adipose tissue dysfunction in humans: a potential role for the transmembrane protein ENPP1.

CONTEXT: Adipose tissue (AT) helps to regulate body fat partitioning and systemic lipid/glucose metabolism. We have recently reported lipid/glucose metabolism abnormalities and increased liver triglyceride content in an AT-selective transgenic model overexpressing ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), the AdiposeENPP1-Tg mouse. OBJECTIVE: The aim of the study was to test the translational hypothesis that AT-ENPP1 overexpression associates with AT dysfunction (changes in AT gene expression, plasma fatty acid, and adipokine levels), increased liver triglyceride deposition, and systemic insulin resistance in humans. DESIGN/SETTING/PARTICIPANTS: A total of 134 young normoglycemic men and women were subjected to body composition studies, hyperinsulinemic-euglycemic clamps, and AT needle biopsy. Twenty men also had liver/muscle nuclear magnetic resonance spectroscopy. MAIN OUTCOME MEASURES: Predetermined measures included AT expression of ENPP1 and other lipid metabolism/inflammation genes, plasma adipokines, and nonesterified fatty acid (NEFA) levels, liver/muscle triglyceride content, and the systemic glucose disposal rate. RESULTS: After statistical adjustment for body fat content, increasing AT-ENPP1 was associated with up-regulation of genes involved in NEFA metabolism and inflammation, increased postabsorptive NEFA levels, decreased plasma adiponectin, increased liver triglyceride content, and systemic insulin resistance in men. In women, there were no changes in plasma adiponectin, NEFAs, or glucose disposal rate associated with increasing AT-ENPP1, despite increased expression of lipid metabolism and inflammation genes in AT. CONCLUSIONS: Increased AT-ENPP1 is associated with AT dysfunction, increased liver triglyceride deposition, and systemic insulin resistance in young normoglycemic men. These findings are concordant with the AdiposeENPP1-Tg phenotype and identify a potential target of therapy for health complications of AT dysfunction, including type 2 diabetes and cardiovascular disease.

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders: Thematic Review Series: Genetics of Human Lipid Diseases.

As the specific composition of lipids is essential for the maintenance of membrane integrity, enzyme function, ion channels, and membrane receptors, an alteration in lipid composition or metabolism may be one of the crucial changes occurring during skeletal and cardiac myopathies. Although the inheritance (autosomal dominant, autosomal recessive, and X-linked traits) and underlying/defining mutations causing these myopathies are known, the contribution of lipid homeostasis in the progression of these diseases needs to be established. The purpose of this review is to present the current knowledge relating to lipid changes in inherited skeletal muscle disorders, such as Duchenne/Becker muscular dystrophy, myotonic muscular dystrophy, limb-girdle myopathic dystrophies, desminopathies, rostrocaudal muscular dystrophy, and Dunnigan-type familial lipodystrophy. The lipid modifications in familial hypertrophic and dilated cardiomyopathies, as well as Barth syndrome and several other cardiac disorders associated with abnormal lipid storage, are discussed. Information on lipid alterations occurring in these myopathies will aid in the design of improved methods of screening and therapy in children and young adults with or without a family history of genetic diseases.