Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice

Abstract

This article is available online at http://www.jlr.org suggests that cardiac dysfunction, arrhythmias, cardiomyopathy, and congestive heart disease could be direct consequences of obesity and leptin resistance, i.e., fatty acid (FA) overload of cardiomyocytes and lipid accumulation in the heart ( 1, 2 ). Studies performed on humans using magnetic resonance spectroscopy indicate that cardiomyocyte fat correlates well with impaired diastolic fi lling, even in seemingly asymptomatic obese volunteers ( 2 ). One of the proposed reasons is that excess FAs or/and their metabolites, i.e., ceramides, induce apoptosis of cardiomyocytes, which is a direct cause of lipotoxic cardiomyopathy and heart failure ( 2, 3 ). The important role for ceramide-induced apoptosis in obesity-related cardiomyopathies has been shown in many animal models, including leptin-insensitive ZDF rats ( 4 ), leptin-defi cient ob/ob mice ( 5, 6 ), and a mouse model of heart disease induced by cardiomyocyte-specifi c overexpression of acyl-CoA synthase ( 7 ). Many maneuvers that reduce ectopic deposition of lipids, i.e., exercise, caloric restriction, and troglitazone, were shown to signifi cantly improve cardiac function in obesity, which additionally implies that steatosis might be a primary reason for cardiac dysfunction ( 2, 8 ).Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme catalyzing the biosynthesis of monounsaturated FAs and has been shown to be a key regulatory factor of body adiposity ( 9 ). Mice with a targeted disruption in the SCD1 gene have increased energy expenditure and insulin sensitivity and are resistant to diet-induced obesity ( 10, 11 ). SCD1 is involved in regulation of ceramide metabolism. Lack of SCD1 reduces the mRNA level and activity of serAbstract The heart of leptin-defi cient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoylCoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1؊ / ؊ mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin defi ciency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA ␤ -oxidation is also signifi cantly lower in the heart of ob/ ob;SCD1 ؊ / ؊ mice compared with ob/ob controls. Moreover, SCD1 defi ciency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by...

Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: Improving the safety of iPS cell transplantation to myocardium

“…50 Inhibition of SCD with PluriSin#1 induced apoptosis of proliferative Nanog-positive iPSD, but not terminally differentiated (non-proliferative) iPS cell-derived CM. Dobrzy P et al 51 demonstrated that gene knockout of SCD-1 improved cardiac function in obese leptin-deficient mice. We also found that PluriSin#1-treated iPS cell-derived CM can engraft and survive in ischemic myocardium at 2 wk after cell transplantation.…”

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

“…In support of this notion, cardiac SREBP-1 was shown to activate the G protein-coupled inwardly reflecting K ϩ channel (GIRK1/4), leading to enhanced acetylcholinesensitive K ϩ currents and reduced arrhythmias post-myocardial infraction (46). Additionally, myocardial FAS and SCD1 were shown to be involved in the regulation of the ability of the heart to respond to stress through a process that appears to involve the activation of Ca 2ϩ /calmodulin-dependent protein kinase II (50) and cause a shift in substrate metabolism toward a preference for glucose utilization (14,16), respectively. Thus it is possible that increased lipogenesis is the first and necessary step in the development of maladaptive LV hypertrophy, and a lack of activation of lipogenic genes, as we found in AAB-induced LV hypertrophy, may lead to pathological events that eventually result in heart dysfunction.…”

“…The lack of SCD1 expression decreases FA uptake and oxidation and increases glucose transport and oxidation in the heart (16). Disruption of the SCD1 gene improves the cardiac function in obese leptin-deficient ob/ob mice by correcting the systolic and diastolic dysfunction (14). The improvement is associated with the reduced expression of the genes involved in FA transport and lipid synthesis within the heart in addition to the reduction of the cardiac free fatty acid (FFA), diacylglycerol (DAG), triglyceride (TG), and ceramide levels (14).…”

“…Disruption of the SCD1 gene improves the cardiac function in obese leptin-deficient ob/ob mice by correcting the systolic and diastolic dysfunction (14). The improvement is associated with the reduced expression of the genes involved in FA transport and lipid synthesis within the heart in addition to the reduction of the cardiac free fatty acid (FFA), diacylglycerol (DAG), triglyceride (TG), and ceramide levels (14). Taken together, all of these data show that although the myocardium has a low capacity for de novo lipogenesis, lipogenic genes and lipids play significant roles in the control of cardiac metabolism and remodeling.…”

Scd1 Plays a Tumor-Suppressive Role in Survival of Leukemia Stem Cells and the Development of Chronic Myeloid Leukemia

“…For stem cell analysis, five mice from each experimental group were sacrificed at day 14 after BMT to collect bone marrow cells. Red blood cells (RBCs) were depleted using RBC lysis buffer (containing NH 4 Cl, KHCO 3 , and EDTA). To stain the cells with antibodies, bone marrow cells were suspended in staining medium (Hanks balanced salt solution with 2% heat-inactivated calf serum), followed by incubation with biotin-labeled lineage antibody cocktail containing a mixture of antibodies against CD3, CD4, CD8, B220, Gr-1, Mac-1, and Ter119 at 4°C for 15 min.…”