Severe Hyperlipidemia Research Articles

Abstract 228: FADS2 Regulates Cardiometabolic Risk Phenotypes in Mice

Single nucleotide polymorphisms of the FADS2 gene associate with cardiometabolic risk in humans. Additionally, serum fatty acid profiles reflecting hepatic hyperactivity of the FADS2 gene product, delta-6 desaturase (D6D), correspond to cardiometabolic syndrome (CMS) phenotypes in humans and animal models. D6D catalyzes rate-limiting steps in essential polyunsaturated fatty acid (PUFA) metabolism, but its role in the pathogenesis of CMS has not been defined. In the present study, we employed pharmacological and genetic gain- and loss-of-function approaches to investigate the links between D6D activity and CMS phenotypes in mice. Transgenic overexpression (TG) of FADS2 in normal (FVB) mice modestly increases hepatic D6D protein expression and serum PUFA product/precursor ratios reflecting greater enzyme activity in vivo . FADS2 TG mice develop a mild, but progressive obesity and insulin resistance with age compared to WT mice, as well as elevated serum triglycerides and LDL/HDL and hepatic macrophage infiltration, but not hepatic steatosis. Global FADS2 ablation prevents obesity/insulin resistance and hyperlipidemia induced by high-fat feeding in C57Bl/6J mice, but promotes severe hepatic steatosis. Pharmacological D6D inhibition in vivo with SC-26196 (100 mpk 4-8 weeks) ameliorates hepatic inflammation and glucose intolerance in FADS2 TG mice and leptin-deficient ( ob ) mice, and prevents severe hyperlipidemia and atherosclerosis in ldlr -/- mice fed an atherogenic diet; despite augmenting hepatic steatosis in all cases. Tissue phospholipid analyses across these models revealed consistent positive relationships between D6D activity, pro-inflammatory eicosanoid accumulation, and a higher phosphatdiylcholine/phosphatidylethanolamine (PC/PE) ratio previously linked to increased hepatic VLDL synthesis and release. These studies establish an important role of D6D activity in the development of CMS and inflammation, and reveal novels links with tissue phospholipid class distribution and metabolism relevant to the development an atherogenic serum lipid profile, hepatic lipid homeostasis, and perhaps other aspects of cardiovascular risk currently under investigation in our laboratory.

The effectiveness of combined therapy of dyslipidemia by atorvastatin and biologycally active substances from marine hydrobionts

Introduction. The perspective direction in therapy of dyslipidemia (DLP) is a complex application of biologycally active substances from marine hydrobionts. Objective. The purpose of research - to compare the lipidcorrective action of preparates based on biologically active substances from marine hydrobionts - fukolam and maristim - individually and in combination with atorvastatin in patients with DLP. Materials and methods. 250patients with DLP and 40 healthy donors were included in research. As medicines atorvastatin, fukolam, maristim were used. In the blood serum the levels of lipid spectrum were determined. Results. Hypolipidemic action of fukolam in complex of basic therapy of patients with DLP was implemented by gradually reducing the total cholesterol, cholesterol of low-density lipoproteins, triglycerides levels to control values. The efficacy of fukolam was comparable with that of atorvastatin in a daily dose of 10 mg. Complex of «fukolam-maristim» showed hypolipidemic effect in severe hyperlipidemia. Conclusions. Combined therapy with use of bioactive substances of natural origin may be one of the way to improve the efficiency of hypolipidemic therapy. We have developed the algorithm of differential correction of DLP by inclusion the fukolam and maristim in complex therapy.

226 The impact of nadph oxidase 2 inhibition on skeletal muscle pathophysiology of atherosclerotic mice

IntroductionApolipoprotein E-deficient mice (ApoE-/-) develop severe hyperlipidaemia and atherosclerotic lesions throughout the aortic root, features that are aggravated by atherogenic diets. NADPH oxidase 2 (Nox2) is an important enzymatic source...

Simvastatin ameliorates memory impairment and neurotoxicity in streptozotocin-induced diabetic mice

Diabetes comes with an additional burden of moderate to severe hyperlipidemia, but little is known about the effects of lipid-lowering therapy on diabetic complications such as diabetes-associated cognitive decline. Herein we investigated the effects of statins on memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Our data indicated that oral administration of simvastatin at 10 or 20mg/kg for 4weeks significantly ameliorated diabetes-associated memory impairment reflected by performance better in the Morris water maze and Y-maze tests. The further study showed that these treatments caused significant increase of peroxisome proliferator-activated receptors gamma and decrease of NF-κB p65 in nucleus of hippocampus and cortex, and ameliorated neuroinflammatory response as evidenced by less Iba-1-positive cells and lower inflammatory mediators including IL-1β, IL-6 and TNF-α as well as suppressed neuronal apoptosis as indicated by decreased TUNEL-positive cells, increased ratio of Bcl-2/Bax and decreased caspase-3 activity in the hippocampus and cortex. Moreover, simvastatin pronouncedly attenuated amyloidogenesis by decreasing amyloid-β, amyloid precursor protein (APP) and beta-site APP cleaving enzyme-1. As expected, treated with simvastatin, the diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. Our findings disclosed novel therapeutic potential of simvastatin for the diabetes-associated cognitive impairment.

Abstract 28: Apolipoprotein A-I Vascular Gene Therapy Provides Durable Protection from Atherosclerosis in Hyperlipidemic Rabbits

Background: Gene therapy, delivered directly to the vascular wall, could potentially protect against atherosclerotic lesion growth or regress existing lesions. Previously, we demonstrated that infusion of HDAdApoAI [a helper-dependent adenoviral vector (HDAd) expressing apolipoprotein (apo) A-I] in carotid arteries of fat-fed rabbits reduced early carotid atherosclerosis development (4 wk after vector infusion). Here we tested whether the same HDAd could protect long-term against more severe atherosclerosis. Methods: 25 fat-fed rabbits underwent bilateral carotid gene transfer [HDAdApoAI on one side; control vector (HDAdNull) on the other, with sides randomized]. Postoperatively, diets were adjusted to maintain plasma cholesterols of 200-800mg/dl. This protocol yields large lipid- and macrophage-rich lesions. 6 mo later, carotids were harvested for analyses of DNA, RNA, protein, cholesterol, and histology (H&E, oil red O), or immunostaining for macrophages, muscle actin, T-cells, ICAM-1 and VCAM-1. Results: Vector genomes persisted equally in HDAdApoAI and HDAdNull-infused arteries; however, apoA-I mRNA was detected only in HDAdApoAI-infused arteries. HDAdApoAI-infused arteries had ~60% less median intimal lesion volume than HDAdNull-infused arteries, with concomitant reductions (40-75%) in intimal lipid, macrophage, smooth muscle cell, VCAM-1 and ICAM-1. We used within-rabbit paired analyses to control for high correlations of lesion size and composition between left and right carotids of the same rabbit. 19 of 25 rabbits had smaller lesions in HDAdApoAI-infused vs HDAdNull-infused arteries; median decreased intimal area between paired carotids in the same rabbit was 30% ( P <0.03). Within individual rabbits, intimal lipid, macrophage, smooth muscle cell, VCAM-1 and ICAM-1 were all less in HDAdApoAI arteries (median 23-36% less; P <0.05 for all except ICAM-1). Conclusions: Vascular gene therapy with HDAdApoAI reduced lesion development and decreased intimal lipid, macrophage, and adhesion molecule expression 6 mo after treatment. Vector genomes and apo A-I mRNA remained high at 6 mo. A single application of vascular gene therapy durably retards development of atherosclerosis, even in a setting of severe hyperlipidemia.

Endothelial Mineralocorticoid Receptors Contribute to Sex‐Dependent Vascular Inflammation and Plaque Vulnerability in Atherosclerosis

BACKGROUNDIschemic complications of atherosclerosis are the leading cause of death in the USA. Ischemic events, including heart attacks and strokes, are predominantly caused by rupture and thrombosis of inflamed or “vulnerable” atherosclerotic plaques. Clinical studies show that excess of the hormone aldosterone predisposes to cardiovascular ischemia and that inhibition of the aldosterone‐binding mineralocorticoid receptor (MR) prevents these adverse outcomes. We previously showed that MR is expressed in human vascular endothelial cells (ECs) and contributes to leukocyte adhesion to ECs in culture.We hypothesize that EC‐specific MR promotes vascular inflammation in hyperlipidemia, thereby contributing to development of atherosclerotic plaques with a vulnerable phenotype.METHODS & RESULTSWe first investigated the effect of whole‐body MR inhibition with spironolactone (Spiro) on vascular inflammation in the ApoE‐KO atherosclerotic mouse model fed high fat diet (HFD) for 8 weeks. Using flow cytometry to quantify specific leukocyte populations in the aortic arches of male ApoE‐KO mice, preliminary results reveal that Spiro reduces total leukocytes, T cells, and monocytes within the aortic arch by up to 80% compared to vehicle. In vitro treatment of human coronary artery ECs with oxidized phospholipids to mimic atherogenic conditions increased leukocyte adhesion by 50% (p<0.01), which was blocked by pretreatment with Spiro. This suggests that MR in ECs contributes to leukocyte adhesion in dyslipidemia. To explore the role of EC‐MR in vascular inflammation due to hyperlipidemia in vivo, transgenic mice with MR specifically deleted from ECs (VE‐Cadherin Cre x floxed MR) were injected with an adeno‐associated virus expressing human PCSK9 (AAV‐PCSK9) and fed HFD for 12 weeks, resulting in severe hyperlipidemia (fasting cholesterol >1000 mg/dL) and atherosclerosis. Cardiovascular risk factors and other potential confounders were measured: there was no difference in serum cholesterol, fasting glucose, body weight gain, blood pressure, or serum aldosterone levels between EC‐MR‐KO and MR‐intact mice of the same sex. Histologic analysis of plaques in the aortic root revealed that EC‐MR‐KO did not affect overall plaque size. However in EC‐MR‐KO mice of both sexes, plaque lipid content tended to be lower (p=0.09) and inflammatory marker staining was reduced (p=0.05), a phenotype consistent with more stable plaques with EC‐MR KO. Quantitative flow cytometry analysis of cells in the aortic arch revealed that EC‐MR‐KO males had a 40% reduction in total leukocytes (p<0.05) and monocytes (p=0.05) compared to MR‐intact males. MR‐intact females had 50–60% fewer intravascular leukocytes (p<0.001), T cells (p<0.01), and monocytes (p<0.01) than MR‐intact males, and this was not further decreased by EC‐MR KO.CONCLUSIONSMR inhibition attenuates atherosclerotic plaque inflammation in male mice. Endothelial MR contributes directly to leukocyte adhesion to ECs in vitro and to plaque inflammation in vivo in dyslipidemic males. Females are protected from vascular inflammation even with intact EC‐MR. Our results suggest a new mechanism for the higher incidence of cardiovascular ischemia and death in people with increased MR activation and for sex differences in the incidence of ischemic cardiovascular events. Further studies are underway to determine the mechanisms for the proinflammatory role of EC‐MR in atherosclerosis and for the observed sex difference.Support or Funding InformationThis work was funded by: NIH/NHLBI HL095590 (to IZJ) and AHA EIA18290005 (to IZJ)

A 1-month-old infant with chylomicronemia due toGPIHBP1gene mutation treated by plasmapheresis

Chylomicronemia is a severe type of hypertriglyceridemia characterized by chylomicron accumulation that arises from a genetic defect in intravascular lipolysis. It requires urgent and proper management, because serious cases can be accompanied by pancreatic necrosis or persistent multiple organ failure. We present the case of a 1-month-old infant with chylomicronemia treated by plasmapheresis. His chylomicronemia was discovered incidentally when lactescent plasma was noticed during routine blood sampling during a hospital admission for fever and irritability. Laboratory investigation revealed marked triglyceridemia (>5,000 mg/dL) with high chylomicron levels. We therefore decided to perform a therapeutic plasmapheresis to prevent acute pancreatitis. Sequence analysis revealed a homozygous novel mutation in exon 4 of GPIHBP1: c.476delG (p.Gly159Alafs). Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) stabilizes the binding of chylomicrons near lipoprotein lipase and supports lipolysis. Mutations of GPIHBP1, the most recently discovered gene, can lead to severe hyperlipidemia and are known to make up only 2% of the monogenic mutations associated with chylomicronemia. The patient maintains mild hypertriglyceridemia without rebound after single plasmapheresis and maintenance fibrate medication so far. Here, we report an infant with chylomicronemia due to GPIHBP1 mutation, successfully treated by plasmapheresis.

Cardiac structural remodeling in hypertensive cardiomyopathy.

Heart failure with preserved ejection fraction (HFpEF), which is a primary driver of morbidity and mortality, accounts for approximately half of all heart failure cases. Therefore, it is essential to develop preclinical animal models for HFpEF pharmacological treatment strategies. We created a porcine model of severe hypertension and hyperlipidemia by using a combination of deoxycorticosterone acetate (DOCA, 100 mg kg-1), Western diet (WD) and angiotensin II infusion. Systolic blood pressure, echocardiography and invasive pressure-volume loop were assessed at baseline, 12 weeks and 18 weeks. A detailed histological assessment was also performed to determine the cardiac structural remodeling. Compared with controls (n=10), hypertensive animals (n=10) showed markedly higher systolic blood pressure (181 vs. 86 mm Hg) at 18 weeks. Concentric remodeling, characterized by a normal chamber size with a thicker wall, was observed in hypertensive animals. Left ventricle diastolic function showed a tendency toward decline, according to the echocardiographic data. Hemodynamic data showed that the end-diastolic pressure-volume relationship was elevated without changes in the end-systolic pressure-volume relationship. Histological results revealed that the fibrotic area in hypertensive animals (P<0.05 vs. controls) and the fibrotic area in the posterior wall of hypertensive animals' left atria were larger than other sites of the left atria (P<0.05 vs. other sites). This model can mimic clinical HFpEF to some degree. We found that the posterior wall of the left atrium is more susceptible to atrial remodeling associated with hypertension compared with other regions of the left atrium.

Lipoprotein-X in cholestatic patients causes xanthomas and promotes foam cell formation in human macrophages

Lipoprotein-X (Lp-X) is an abnormal phospholipid-rich lipoprotein found in patients with cholestatic liver disease. Some patients exhibit skin xanthomas and severe hyperlipidemia. We investigated whether Lp-X induces foam cell formation in human-derived macrophages. To compare the atherogenic properties of Lp-X and modified LDL, we isolated Lp-X from 2 patients who had drug-induced cholestasis and xanthoma striata in the interphalangeal folds. We prepared oxidized LDL and acetylated LDL from healthy volunteers for the positive control experiments. When human monocyte-derived macrophages were incubated with these lipoproteins, the isolated Lp-X induced more prominent lipid accumulation than oxidized LDL or acetylated LDL. One case underwent liver biopsy, with the bile ducts showing marked damage, fulfilling the criteria for vanishing bile duct syndrome. The other case was clinically diagnosed as drug-induced hypersensitivity syndrome. In both cases, Lp-X levels decreased markedly and the xanthomas disappeared completely after the improvement of cholestasis. This study indicates that Lp-X induces foam cell formation in human-derived macrophages. Our findings strongly suggest that persistently elevated Lp-X may cause xanthomas.

Lipoprotein-X disease in the setting of severe cholestatic hepatobiliary autoimmune disease

Severe cholestatic disease and hyperlipidemia are both commonly encountered by medical professionals. This article reviews the current pathophysiological model of lipoprotein-X syndrome related to 3 cases from 2 academic medical centers in the United States.

Heydeʼs Syndrome: An Integrative Disease

Heyde's syndrome is an integrative disease process that involves gastrointestinal bleeding, von-Willebrand's factor, and aortic stenosis. First described in 1958 through simple observations from an internist, its etiological description has since evolved, with clinical and bench research now indicating quite elegant pathophysiological underpinnings. We here present a case of Heyde's syndrome resulting in recurrent gastrointestinal bleeding. A 68-year-old Caucasian woman with medical comorbidities of coronary artery disease, severe aortic stenosis, hypertension, hyperlipidemia, and diabetes mellitus type 2 presented with 2 day onset of worsening chest pain and exertional dyspnea. On further inquiry, the patient also reported multiple dark bowel movements over the preceding three days. Initial laboratory values were significant for severe anemia (Hemoglobin of 7.1gm/dL). The patient was admitted for severe symptomatic anemia. A transthoracic echocardiogram revealed severe aortic stenosis (Figure 1). The patient underwent bidirectional endoscopy which demonstrated multiple arteriovenous malformations (AVMs) requiring the use of argon plasma coagulation and injection of epinephrine to achieve hemostasis. The patient was subsequently referred for expedited aortic valve replacement. It is quite infrequent that the disciplines of gastroenterology, hematology and cardiology intersect with each other in regards to forming pathophysiological basis of a disease. Heyde's syndrome represents one such example. Loss of Von-Willebrand factor (a high molecular weight protein multimer that is involved in primary hemostasis) in patients with severe aortic stenosis, is implicated in the pathogenesis. It is now believed that high-velocity flow through a stenotic aortic valve causes conformational change in the configuration of large molecular weight von-Willebrand factor, making it vulnerable to cleavage by the plasma protein ADATS13 and subsequently rendering it hemostatically inferior to the normal high molecular weight multimers. Von-Willebrand factor may have also an essential role in maintaining vascular integrity which could explain the development of angiodysplasias in patients with deficiency of this factor. Aortic valve replacement was shown to improve the levels of Von-Willebrand factor significantly and is considered the definitive treatment for Heyde's syndrome.Figure 1

Matrine ameliorates adriamycin-induced nephropathy in rats by enhancing renal function and modulating Th17/Treg balance

Matrine (MAT) is an active alkaloid extracted from Radix Sophora flavescens. The present study was to investigate whether MAT could effectively treat Adriamycin-induced nephropathy (AIN). AIN was induced in rats using a single injection of Adriamycin (ADR). Renal interleukin-6 (IL-6), IL-10, IL-17 and transforming growth factor-β (TGF-β) levels, and the expression of forkhead box protein 3 (Foxp3) and retinoid-related orphan nuclear receptor γt (Rorγt) was measured. AIN rats developed severe albuminuria, hypoalbuminaemia, hyperlipidaemia and podocyte injury. Daily administration of MAT (100mg/kg or 200mg/kg) significantly prevented ADR-induced podocyte injury, decreased AIN symptoms and improved renal pathology manifestations. Of note, treatment with MAT (100mg/kg) plus prednisone (Pre, 5mg/kg) had equivalent efficacy to that of Pre alone (10mg/kg). Additional findings showed that ADR triggered a disordered cytokine network and abnormal expression of Foxp3 and Rorγt in rats, as reflected by increased levels of IL-6, IL-10, TGF-β, Rorγt and decreased levels of IL-10 and Foxp3. Interestingly, MAT weakened the disordered cytokine network and normalized the expression of Foxp3 and Rorγt. In addition, a significant negative correlation was observed between the values of Foxp3/Rorγt and renal pathology scores. Finally, MAT normalized regulatory T cells (Treg)/ T-helper17 cells (Th17) ratio in peripheral blood mononuclear cells of AIN rats. These data indicate MAT prevents AIN through the modification of disordered plasma lipids and recovery of renal function, and this bioactivity is at least partly attributed to the suppression of renal inflammation and the regulation of the Treg/Th17 imbalance.

Abstract P291: High Fat Diet Promotes Hypertension and Vascular Remodeling but Not Vascular Fibrosis or Altered Contractility in Dahl Salt Sensitive Rats

Obesity associated hypertension in rodent models is commonly associated with altered vascular reactivity to sympathetic neurotransmitters and inflammation-induced vascular remodeling/fibrosis. Dahl salt-sensitive (SS) rats exhibit elevated sympathetic activity and vascular remodeling. We hypothesized that diet-induced obesity in Dahl SS rats would promote hypertension, vascular dysfunction and remodeling/fibrosis. Male Dahl SS rats were placed on high fat diet (HFD, 60% kcal from fat with final concentrations of 0.33% NaCl and 1% K + , n=5) or normal-fat diet (NFD; 10% kcal from fat, 0.24% NaCl, 0.36% K + , n=5) for 24-26 weeks after weaning (3 weeks of age). Compared with NFD rats, HFD rats displayed severe hypertension (MAP, 165±4 mmHg vs 133±6 mmHg, P&lt;0.05), higher body-weight (470±6g vs 433±7g, P&lt;0.05), and hyperlipidemia (cholesterol, 211±22 mg/dl vs 138±23 mg/dl, P=0.05). HFD rats did not show significant changes in plasma levels of fasting glucose (85±5 mg/dl vs 75±5 mg/dl), insulin (2.6±0.8 ng/ml vs 2.2±1.1 ng/ml), leptin (0.77±0.18 ng/ml vs 0.44±0.06 ng/ml), or aldosterone (249±3 pg/ml vs 234±3 pg/ml) (all P&gt;0.05). HFD did not affect pressurized mesenteric arterial (~300 μm inner diameter, 60 mmHg) reactivity to norepinephrine or ATP in vitro . Pressurized mesenteric arteries from HFD rats displayed thicker walls (Ca 2+ free buffer, 40±1 μm vs 36±1 μm, P&lt;0.05), but showed slightly increased distensibility. Morphological studies did not reveal greater fibrosis in adventitia of mesenteric, intrarenal and coronary arteries from HFD rats. However, HFD induced inflammation in mesenteric perivascular adipose tissue, as shown by increased CD3 positive cell infiltration and histological evidence of fibrosis and angiogenesis. Our studies indicate that HFD in male Dahl SS rats promotes hypertension, perivascular adipose tissue inflammation and vascular remodeling, but not vascular fibrosis. Alteration of vascular contractility to sympathetic neurotransmitters, however, is not required for obesity associated hypertension in Dahl SS rats.

Microangiopathic Occlusion of a Perforating Prepontine Long Circumferential Artery Presenting with Lower Motor Neuron Facial Weakness: Clinical and Radiological Correlation

Case Description: A 79-year old male patientwith myelodysplastic syndrome associated with severe neutropenia, thrombocytopenia, anemia, hypertension, and hyperlipidemia was admitted for pneumonia secondary to influenza A. Two weeks later he presented with new symptoms of acute dysarthria, and left facial weakness involving his upper and lower face; the following day he developed left arm weakness. Admission computed tomography (CT) and MRI scans revealed an acute ischemic stroke (AIS) in the right posterior frontal cortex. The initial MRI was reported negative for pontine lesions. Anatomically, the cortical infarct could not explain his left lower motor neuron cranial nerve VII (LMN CN VII) facial weakness distribution because in a cortical lesion the upper half of the face would be expected spared due to contralateral cortical innervation. Upon review of the MRI, the initial hyperintensity seen on Fluid-Attenuated Inversion Recovery (FLAIR) was overlooked as an acute stroke in the vicinity of the perforating prepontine long circumferential artery affecting the CN VII nucleus. Conclusion: In the absence of earache, active infection, and/or inflammation, a sudden onset facial palsy, lower motor neuron distribution, must point to a pontine microangiopathic infarct until proven otherwise. Under these circumstances, maintaining a high level of suspicion is of paramount importance.

Editorial: A Hand at Work: Effects of Aging.

Editorial: A Hand at Work: Effects of Aging.

Lipodystrophy Due to Adipose Tissue-Specific Insulin Receptor Knockout Results in Progressive NAFLD.

Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels.

Other aspects of bariatric surgery: liver steatosis, ferritin and cholesterol metabolism.

Bariatric surgery developed in the late 1970 to treat severe hyperlipidemias in overweight individuals, not necessarily obese. Several techniques have been developed, and the concept has come first of a surgery for morbid obesity, then of a cure for diabetes in morbid obesity. There are other aspects of bariatric surgery that deserve attention, beyond BMI and diabetes, such as hypertension, poor life expectancy, increased prevalence of cancer, congestive heart failure, social inadequacy. The aim of this presentation is to review some recent development in clinical research, in the fields of liver steatosis, ferritin metabolism, and cholesterol metabolism. Liver steatosis, also called fatty liver encompasses a graduation of diseases with different clinical relevance and prognosis. NAFLD correlates with atherosclerosis, insulin resistance and diabetes mellitus. There is now evidence that weight loss, obtained through diet or restrictive surgery, reduces the prevalence (and the severity) of NAFLD. An other issue is represented by serum ferritin concentrations, that are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients, especially in the presence of obesity. Body iron contributes to excess oxidative stress already at non iron overload concentrations. Moreover, serum ferritin is an important and independent predictor of the development of diabetes. Weight loss is accompanied by reduction of ferritin, more after restrictive than malabsorptive surgery. Metabolic changes are greater after malabsorptive or mixed surgery than after purely restrictive surgery, and this has been ascribed to a greater weight loss. Studies comparing the two kinds of surgery indicate that, for the same amount of weight loss, decrease of cholesterol is greater with the former than with the latter techniques, and this difference is mainly due to a greater reduction of intestinal absorption of cholesterol. In the choice of surgery for the single patient, among other aspects, malabsorptive surgery seems to be more indicated in subjects with hyperlipidemia, especially with high cholesterol levels.

Extensive metabolic disorders are present in APCmin tumorigenesis mice

Wnt signaling plays essential role in mesenchymal stem cell (MSC) differentiation. Activation of Wnt signaling suppresses adipogenesis, but promotes osteogenesis in MSC. Adenomatous polyposis coli (APC) is a negative regulator of β-catenin and Wnt signaling activity. The mutation of APC gene leads to the activation of Wnt signaling and is responsible for tumorigenesis in APCmin mouse; however, very few studies focused on its metabolic abnormalities. The present study reports a widespread metabolic disorder phenotype in APCmin mice. The old APCmin mice have decreased body weight and impaired adipogenesis, but severe hyperlipidemia, which mimic the phenotypes of Familial Adenomatous Polyposis (FAP), an inherited disease also caused by APC gene mutation in human. We found that the expression of lipid metabolism and free fat acids (FA) use genes in the white adipose tissue (WAT) of the APCmin mice is much lower than those of control. The changed gene expression pattern may lead to the disability of circulatory lipid transportation and storage at WAT. Moreover, the APCmin mice could not maintain the core body temperature in cold condition. PET–CT determination revealed that the BAT of APCmin mice has significantly impaired ability to take up 18FDG from the blood. Morphological studies identified that the brown adipocytes of APCmin mice were filled with lipid droplets but fewer mitochondria. These results matched with the findings of impaired BAT function in APCmin mice. Collectively, our study explores a new mechanism that explains abnormal metabolism in APCmin mice and provides insights into studying the metabolic disorders of FAP patients.

New guidelines for screening and management of familial dyslipidemia

Familial dyslipidemia, a frequent genetic cause of premature cardiovascular disease, is still underdiagnosed and undertreated. According to recent European studies, the prevalence of familial hypercholesterolemia is higher than previously suspected and reaches 1/200-300 persons, while familial combined hyperlipidemia affects 1-3% of the population. Screening is important, as familial dyslipidemia often leads to cardiovascular event before 60 years of age, and usual scores of risk are not appropriate for these patients. Screening is recommended in childhood in case of family history of premature cardiovascular disease or severe hyperlipidemia in first degree relatives. Lifestyle modifications, eviction of any additive cardiovascular risk factor and tailored drug therapy are the cornerstones of an optimal management.

Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice

Adipose tissue can store over 50% of whole-body cholesterol; however, the physiological role of adipose tissue in cholesterol metabolism and atherogenesis has not been directly assessed. Here, we examined lipoprotein metabolism and atherogenesis in a unique mouse model of severe lipodystrophy: the Seipin−/− mice, and also in mice deficient in both low-density lipoprotein receptor (Ldlr) and Seipin: the Ldlr−/−Seipin−/− mice. Plasma cholesterol was moderately increased in the Seipin−/− mice when fed an atherogenic diet. Strikingly, plasma cholesterol reached ~6000mg/dl in the Seipin−/−Ldlr−/− mice on an atherogenic diet, as compared to ~1000mg/dl in the Ldlr−/− mice on the same diet. The Seipin−/−Ldlr−/− mice also developed spontaneous atherosclerosis on chow diet and severe atherosclerosis on an atherogenic diet. Rosiglitazone treatment significantly reduced the hypercholesterolemia of the Seipin−/−Ldlr−/− mice, and also alleviated the severity of atherosclerosis. Our results provide direct evidence, for the first time, that the adipose tissue plays a critical role in the clearance of plasma cholesterol. Our results also reveal a previously unappreciated strong link between adipose tissue and LDLR in plasma cholesterol metabolism.