Sterol Regulatory Element-binding Factor 1c Research Articles

Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism.

SummaryMitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c−/−) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.

Impaired fatty acid synthesis affects immune cells activation: focus on sterol regulatory element binding factor-1c on T lymphocytes

Impaired fatty acid synthesis affects immune cells activation: focus on sterol regulatory element binding factor-1c on T lymphocytes

Impaired fatty acid synthesis affects immune cells activation: Focus on sterol regulatory element binding factor-1c on T lymphocytes

Impaired fatty acid synthesis affects immune cells activation: Focus on sterol regulatory element binding factor-1c on T lymphocytes

The lipogenic regulator Sterol Regulatory Element Binding Factor-1c is required to maintain peripheral nerve structure and function.

Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy [1], but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We explored the extent to which lack of the key regulator of FA synthesis as Sterol Regulatory Element Binding Factor-1c (Srebf-1c) could result in the development of peripheral neuropathy. We found that Srebf-1c null mice display a neuropathic phenotype consisting in hypermyelinated small caliber fibers, the result of changes in myelin periodicity. Unexpectedly, transcriptomics and metabolomics revealed activation of peroxisome proliferator activated receptor α (Pparα) signaling in Srebf-1c null peripheral nerve as a result of increased levels of two distinct phosphatidylcholine-based Pparα ligands, PC-C16:0/C18:1 and PC-C18:0/C18:1 [2, 3]. Pparα is a nuclear receptor that directs uptake, utilization and catabolism of FAs [4]. As a consequence of abnormal local Pparα activation, Srebf-1c null peripheral nerve exhibit increased fatty acid utilization, a detrimental condition leading to peripheral neuropathy. Treatment with a Pparα antagonist rescues the neuropathy of Srebf-1c null mice. These findings reveal the importance of FA synthesis to sustain peripheral nerve structure and function.

Lack of Sterol Regulatory Element Binding Factor-1c Imposes Glial Fatty Acid Utilization Leading to Peripheral Neuropathy

Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function.

Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism

Genetic factors that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and associated diabetes and cardiovascular disease are unclear. The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) modulates lipogenesis and insulin sensitivity and was experimentally connected to NAFLD. We assessed the impact of a common SREBF-1c polymorphism on the incidence and severity of NAFLD and on associated glucose and lipoprotein dysmetabolism. We followed up 212 randomly selected, nonobese, nondiabetic, insulin-sensitive participants in a population-based study without NAFLD or metabolic syndrome at baseline who were characterized for the common SREBF-1c gene rs11868035 A/G polymorphism, dietary habits, physical activity, adipokine profile, C-reactive protein (CRP), and circulating markers of endothelial dysfunction. A comparable cohort of NAFLD patients underwent a liver biopsy, an oral-glucose-tolerance test with minimal model analysis of glucose homeostasis variables, and an oral-fat-tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. SREBF-1c predicted the 7-y incidence of NAFLD (OR: 1.71; 95% CI: 1.15, 2.53) and diabetes and the 7-y elevation in CRP and endothelial dysfunction markers. In biopsy-proven NAFLD patients, the SREBF-1c A allele conferred increased risk of severe steatosis and nonalcoholic steatohepatitis; more-severe hepatic, muscle, and adipose tissue insulin resistance; and pancreatic β cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceride-rich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation. SREBF-1c polymorphism is associated with increased risk of developing NAFLD with more severe liver histology and derangement in glucose and lipoprotein metabolism, which contribute to the presentation and natural history of NAFLD.

Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation

Diabetic peripheral neuropathy (DPN) is characterized by myelin abnormalities; however, the molecular mechanisms underlying such deficits remain obscure. To uncover the effects of diabetes on myelin alterations, we have analyzed myelin composition. In a streptozotocin-treated rat model of diabetic neuropathy, analysis of sciatic nerve myelin lipids revealed that diabetes alters myelin's phospholipid, FA, and cholesterol content in a pattern that can modify membrane fluidity. Reduced expression of relevant genes in the FA biosynthetic pathway and decreased levels of the transcriptionally active form of the lipogenic factor sterol-regulatory element binding factor-1c (SREBF-1c) were found in diabetic sciatic nerve. Expression of myelin's major protein, myelin protein zero (P0), was also suppressed by diabetes. In addition, we confirmed that diabetes induces sciatic nerve myelin abnormalities, primarily infoldings that have previously been associated with altered membrane fluidity. In a diabetic setting, synthetic activator of the nuclear receptor liver X receptor (LXR) increased SREBF-1c function and restored myelin lipid species and P0 expression levels to normal. These LXR-modulated improvements were associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. These findings demonstrate an important role for the LXR-SREBF-1c axis in protection from diabetes-induced myelin abnormalities.

A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

Male aromatase knockout mice (ArKO; an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17β-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ERα or ERβ, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ERα- or ERβ-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ERα agonist had normal liver histology and TG contents compared with vehicle-treated ArKO; omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ERβ agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase (Fasn) and stearoyl-coenzyme A desaturase 1 (key enzymes in de novo FA synthesis) were significantly elevated compared with vehicle-treated WT, but only Fasn expression was lowered to WT level after ERα agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for β-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator of de novo FA synthesis). We also confirmed by RT-PCR that only ERα is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ERα to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ERα, estrogens could regulate hepatic functions via peripheral and central pathways.

Garcinia cambogiaExtract Ameliorates Visceral Adiposity in C57BL/6J Mice Fed on a High-Fat Diet

The aim of present study is to evaluate the effects of Garcinia cambogia on the mRNA levels of the various genes involved in adipogenesis, as well as on body weight gain, visceral fat accumulation, and other biochemical markers of obesity in obesity-prone C57BL/6J mice. Consumption of the Garcinia cambogia extract effectively lowered the body weight gain, visceral fat accumulation, blood and hepatic lipid concentrations, and plasma insulin and leptin levels in a high-fat diet (HFD)-induced obesity mouse model. The Garcinia cambogia extract reversed the HFD-induced changes in the expression pattern of such epididymal adipose tissue genes as adipocyte protein aP2 (aP2), sterol regulatory element-binding factor 1c (SREBP1c), peroxisome proliferator-activated receptor gamma2 (PPARgamma2), and CCAT/enhancer-binding protein alpha (C/EBPalpha). These findings suggest that the Garcinia cambogia extract ameliorated HFD-induced obesity, probably by modulating multiple genes associated with adipogenesis, such as aP2, SREBP1c, PPARgamma2, and C/EBPalpha in the visceral fat tissue of mice.

Polymorphisms in the gene encoding sterol regulatory element-binding factor-1c are associated with type 2 diabetes

The sterol regulatory element-binding factor (SREBF)-1c is a transcription factor involved in the regulation of lipid and glucose metabolism. We have previously found evidence that a common SREBF1c single-nucleotide polymorphism (SNP), located between exons 18c and 19c, is associated with an increased risk of type 2 diabetes. The present study aimed to replicate our previously reported association in a larger case-control study and to examine an additional five SREBF1c SNPs for their association with diabetes risk and plasma glucose concentrations. We genotyped six SREBF1c SNPs in two case-control studies (n=1,938) and in a large cohort study (n=1,721) and tested for association with type 2 diabetes and with plasma glucose concentrations (fasting and 120-min post-glucose load), respectively. In the case-control studies, carriers of the minor allele of the previously reported SNP (rs11868035) had a significantly increased diabetes risk (odds ratio [OR]=1.20 [95% CI 1.04-1.38], p=0.015). Also, three other SNPs (rs2236513, rs6502618 and rs1889018), located in the 5' region, were significantly associated with diabetes risk (OR > or =1.21, p< or =0.006). Furthermore, two SNPs (rs2236513 and rs1889018) in the 5' region were weakly (p<0.09) associated with plasma glucose concentrations in the cohort study. Rare homozygotes had increased (p< or =0.05) 120-min post-load glucose concentrations compared with carriers of the wild-type allele. Haplotype analyses showed significant (p=0.04) association with diabetes risk and confirmed the single SNP analyses. In summary, we replicated our previous finding and found evidence for SNPs in the 5' region of the SREBF1c gene to be associated with the risk of type 2 diabetes and plasma glucose concentration.