APOLIPOPROTEIN E IN DIABETES AND METABOLIC SINDROME
The Metabolic Syndrome (MetS) is a complicated metabolic disorder that increases the risk of developing cardiovascular disease and diabetes, and is closely linked to disturbances in lipid and glucose metabolism. Approximately one-fourth of the adult European population has the MetS and a further increase can be anticipated because of projections of a greater prevalence of obesity in the future. Even Spain, former example of Mediterranean Diet, its prevalence escalates up to 40% in certain subpopulations. Apolipoprotein E (APOE) associates with lipoproteins and mediates their metabolism. In humans, the APOE gene is polymorphic and has three alleles, APOE*2, APOE*3 and APOE*4. Carrying the APOE*4 allele has been associated with an increased cardiovascular risk, predisposition to develop Alzheimer’s disease and insulin resistance. Recently, APOE*4 has also been linked with MetS. However, the mechanisms whereby this association occurs are not clear.
The objective of this project is to investigate the role of APOE in the Metabolic Syndrome by employing a multidisciplinary approach. These disciplines include in vivo analysis of transgenic mouse models as well as biochemical and cell biology experiments, coupled with epidemiological analysis of human populations.
PTRF IN ADIPOCYTES
Polymerase I and transcript release factor (PTRF) is a protein highly expressed in adipose tissue and is a component of caveolae. It has been demonstrated that PTRF localizes specifically to a caveolae subclass that metabolizes TAG. Moreover, PTRF interacts with HSL in primary human adipocytes and translocates from the plasma membrane to the cytosol in response to insulin treatment, suggesting that PTRF may function in concert with HSL in the regulation of lipolysis These findings point to a potential role of PTRF in regulating lipid metabolism in adipose tissue.
In this project we will assess the functionality of adipocytes in which PTRF has been either overexpressed or knocked-off by lentiviral transduccion.
EXPANDIBILITY OF THE ADIPOSE TISSUE. BIOMARKERS TO DETERMINE THE LIMIT OF EXPANSION AND THE COMPLICATIONS OF OBESITY.
Obesity is a chronic disease of multifactorial origin defined as an accumulation of fat that causes health problems. The subcutaneous adipose tissue is able to expand during positive energy balance. However, expandability is limited and once surpassed there is an ectopic lipid deposition in other organs, which is the origin of the metabolic disorders associated with obesity.
OBJECTIVES: 1. Study of the biogenesis of subcutaneous adipose tissue, to determine the factors that set the limit of expansion.2. Develop noninvasive biomarkers that can be used in clinical practice to differentiate obese individuals in which the expansion limit has not yet been reached (benign obesity) of those who have exceeded the limit of expansion and require aggressive therapy.
METHODOLOGY: We included patients from the Department of Surgery who will donate a sample of subcutaneous fat (prospective study). Abdominal imaging techniques will be performed to determine the level of adipose tissue expansion, metabolomics in plasma and fat to identify metabolites produced by adipocytes in the process of expansion and transcriptomics in adipose tissue to determine changes in gene expression related with the adipogenic process. Biomarkers of interest will be tested in vitro and in a validation cohort. These biomarkers will decrease the economic and health care burden of obesity on society by allowing an early detection of pathological obese individuals.
HMB FOR DESNUTRITION IN PATIENTS WITH CIRRHOSIS (HEPATIC)
Cirrhosis is a late stage of hepatic fibrosis caused by many forms of liver diseases and conditions, such as hepatitis and chronic alcoholism. WHO has reported that this condition accounts for 1.8% of all deaths in Europe (170,000 deaths/year).
Patients with cirrhosis are characterized by severe metabolic alterations, which converge in a malnutritional state. Malnutrition encompasses glucose intolerance, chronic inflammation, altered gut microbiota, reduced muscle mass (sarcopenia), as well as loss and dysregulation of adipose tissue (adipopenia). Malnutrition is the most frequent complication that adversely affects the outcomes of cirrhotic patients. Yet, despite its clinical repercussions and potential reversibility, there are no effective therapies because our limited understanding of the mechanisms underlying this altered metabolism.
β-hydroxy β-methylbutyrate (HMB) is a naturally produced substance regarded as safe and effective in preventing muscle loss during chronic diseases. Previous studies have indicated some beneficial effects of HMB itself or its parent metabolite, leucine, on adipose tissue, glucose intolerance, inflammation, and gut microbiota. For this project we aim to translate those beneficial effects to cirrhotic patients. We hypothesize that HMB can improve cirrhosis-related metabolic abnormalities through its pleiotropic effects. The goals of this proposal are:
i) to perform a randomized clinical trial to evaluate the efficacy of HMB, administered as nutritional supplementation, on clinical symptoms of cirrhosis.
ii) to uncover the precise metabolic pathways that underlie HMB action, with a special focus on muscle, adipose tissue, and gut microbiota.
For this project we have put together a multidisciplinary team aimed to test HMB as a novel adjuvant therapy for cirrhotic patients and provide new molecular targets for the prevention or treatment of the metabolic dysregulation associated to liver cirrhosis.
LIPOPROTEIN PROFILING 4 HCV INFECTION
Hepatitis C Virus (HCV) associates with lipoproteins being secreted from the liver as highly infective lipoviro particles (LVP). These LVP markedly interfere with the host lipid metabolism, ultimately causing a wide array of extrahepatic manifestations of chronic infection such as liver steatosis and cardiovascular disease (CVD). Characterizing this impaired lipid homeostasis is hence of vital importance. Yet, previous research investigating the interaction of HCV genotypes and direct-acting antiviral (DAA) treatments on lipid metabolism leaves some aspects not yet addressed. We hypothesize that measuring the number and size of lipoprotein subclasses will provide a better tool to address HCV-mediated lipid remodeling rather than the classical measures of lipoprotein-borne cholesterol. Additionally, APOE is a structural component of HCV-LVP and plays important roles in HCV infection and virion assembly. However, previous epidemiological studies have also showed conflicting results regarding the differential role of APOE isoforms on circulating lipoproteins after DAA treatments. We hypothesize that those discrepant results may result as not-yet known interactions between APOE genotypes and HCV genotypes and their modulation by HCV treatments.
The aim of this study will be 1) to clinically and epidemiologically characterize the dyslipidemia caused by the HCV as well as the persistence of the altered lipid profile after the most common DAA treatments with the application of the DOSY method to calculate lipoprotein number and size, and 2) evaluate how polymorphisms in the APOE are associated with the HCV- and DAA- mediated lipid remodeling, accounting for HCV genotypes and different DAA treatments as confounding factors.