Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

Soluble guanylate cyclase chronic stimulation effects on cardiovascular reactivity in cafeteria diet-induced rat model of metabolic syndrome.

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 µM)) and thoracic aorta (phenylephrine (1 nM-10 µM), acetylcholine (1 nM-10 µM), and sodium nitroprusside (SNP) (0.1 nM-0.1 µM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in ß-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α1-adrenoceptor-induced vasoconstriction, and restored cardiac inotropy and coronary vasodilation. These findings suggest that BAY 41-2272 may be a potential novel drug for preventing metabolic and cardiovascular complications of metabolic syndrome.

Integrin ß3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion.

OBJECTIVE: Integrin ß3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether ß3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with ß3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an αIIb deficiency or healthy subjects. The ß3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that ß3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine)720-722 motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/ß3/LPL complex that is required for ß3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in ß3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH720-722-mutated ß3 genes. CONCLUSIONS: This study reveals a hypertriglyceridemia in both ß3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of ß3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with ß3-deficient Glanzmann thrombasthenia.

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism.

The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.

Clinical and functional studies of two novel variants in the LPL gene in subjects with severe hypertriglyceridemia.

BACKGROUND: Two novel variants (p.Arg270Gly and p.Asp308Glyfs*3) in the LPL gene have recently been identified in subjects with hypertriglyceridemia (HTG). In this study, we investigated clinical and genetic features of their families and examined the functional significance of these two variants in vitro. METHODS: Clinical and genetic data were collected. Site-directed mutagenesis and transient expression in cld cells were performed. Lipoprotein lipase (LPL) mass and activity were measured. RESULTS: In vitro studies showed that LPL mass and activity in the media of cells transfected with the p.Arg270Gly variant were significantly reduced. In the cell lysates, however, LPL mass was preserved but LPL activity was reduced, suggesting that the LPL defect was in the secretion and activity. For the p.Asp308Glyfs*3 variant, LPL mass in the cell lysate was relatively preserved compared to that of the wild-type, while LPL mass in the media was decreased albeit not significantly. LPL activities in the cell lysate and in the media of cells transfected with this variant were significantly reduced, suggesting that the p.Asp308Glyfs*3 variant might affect the activity, and possibly, secretion of LPL. CONCLUSIONS: These novel variants in the LPL gene were likely pathogenic with the defect in secretion and/or activity.

Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.

BACKGROUND AND AIMS: Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms. METHODS AND RESULTS: A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein. CONCLUSION: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.

A common variant in ARHGEF10 alters delta-6 desaturase activity and influence susceptibility to hypertriglyceridemia.

BACKGROUND: Numbers of single nucleotide polymorphisms (SNPs) associated with fatty acid desaturase activities have been previously identified within the FADS1-FADS2 gene cluster, which encodes delta-5 (D5D) and delta-6 (D6D) desaturases, respectively. OBJECTIVE: We aimed at further characterizing the genetic variability associated with D5D and D6D activities on a genome-wide scale. METHODS: We conducted a genome-wide association study of D5D and D6D activities in a cohort of 141 individuals from the greater Quebec City metropolitan area using the Illumina HumanOmni5-Quad BeadChip. Estimates of D5D and D6D activities were computed using product-to-precursor fatty acid ratios, arachidonic acid (AA)/dihomo-gamma-linolenic acid (DGLA) for D5D, and DGLA/linoleic acid (LA) for D6D. Levels of fatty acids were measured by gas chromatography in plasma phospholipids. RESULTS: We identified 24 previously reported SNPs associated with fatty acid levels and desaturase activities as significantly associated with D5D activity within the FADS1-FADS2 gene cluster (lead SNP rs174566/A>G). Furthermore, we identified 5 novel loci potentially associated with D5D activity at chromosomes 1, 6, 4, 8 and 19. A novel SNP associated with D6D activity and mapped to the ARHGEF10 locus (rs2280885/A>G) was identified, with carriers of the rare allele showing a significant increase in D6D activity and plasma triglyceride levels. After multiple testing correction by permutation, only rs174566 and rs2280885 remained significantly associated to D5D and D6D activity estimates, respectively. CONCLUSIONS: These results confirm previous genetic associations within the FADS1-FADS2 gene cluster with D5D activity. A novel genetic variation associated with higher D6D activity within the ARHGEF10 gene is potentially altering plasma triglyceride levels.

Extreme hypertriglyceridemia, pseudohyponatremia, and pseudoacidosis in a neonate with lipoprotein lipase deficiency due to segmental uniparental disomy.

Extreme hypertriglyceridemia is rare in the neonatal period. We report a neonate with lipoprotein lipase (LPL) deficiency who presented with diagnostic and management conundrum. A full-term 36-day-old female was noted to have "Pepto-Bismol like" blood when repeating a newborn screening. The initial plasma triglyceride level was 24,318 mg/dL. The laboratory tests revealed serum bicarbonate level of <5 mmol/L, sodium of 127 mmol/L, and severe anemia. There were no signs of acute distress. The point of care capillary blood testing, however, demonstrated normal serum pH (7.2), bicarbonate (25.4 mmol/L), and sodium (139 mmol/L). The patient had mild elevation of serum lactic acid and no ketonuria. A diagnosis of type I hyperlipoproteinemia was made. Oral feeding was stopped, and the infant received intravenous fluids for the next 7 days resulting in lowering of serum triglyceride levels to 1016 mg/dL. Oral feeding was initiated with an amino acid-rich formula to which medium chain triglycerides were slowly added, while maintaining the total fat content to <15% of total daily energy. Sequencing of the LPL gene revealed a homozygous c.644G>A, p.(Gly215Glu) mutation. Subsequent analysis of the parental samples revealed that only the father, but not the mother, was a heterozygous carrier of the same mutation. Analysis of 18 informative microsatellite markers on chromosome 8 revealed paternal segmental uniparental disomy with partial absence of the maternal chromosome 8p, confirmed by single-nucleotide polymorphism microarray. We conclude that besides pseudohyponatremia, extreme hypertriglyceridemia can rarely present as pseudoacidosis and uniparental disomy can be an underlying mechanism for autosomal recessive diseases such as LPL deficiency.

Non-accidental Trauma Work-up: Unusual Retinal Finding Leads to a Rare Diagnosis.

Lipoprotein lipase (LPL) deficiency is an autosomal recessive condition due to absent or decreased activity of LPL enzyme. The LPL deficiency is a rare condition that is mainly diagnosed in children, but there is no standard screening method at this time. In our report, we describe a 6-day-old male infant who was found to have hypertriglyceridemia after lipemia retinalis was diagnosed from a fundoscopic examination for nonaccidental trauma work-up. After dietary modification was done, his triglyceride levels decreased significantly, and there were no complications. When diagnosed later in life, recurrent pancreatitis can be a significant complication.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia.

Low-density lipoprotein (LDL) cholesterol plays a pivotal role in the pathogenesis of atherosclerotic cardiovascular disease (CVD). The discovery that proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a key regulator pathway for hepatic LDL receptor (LDLR) degradation sheds light on new uncovered issues regarding LDL-C homeostasis. Indeed, as confirmed by phase II and III clinical trials with monoclonal antibodies, targeting PCSK9 represents the newest and most promising pharmacological tool for the treatment of hypercholesterolemia and related CVD. However, clinical, genetic, and experimental evidence indicates that PCSK9 may be either a cause or an effect in the context of metabolic syndrome (MetS), a condition comprising a cluster of risk factors including insulin resistance, obesity, hypertension, and atherogenic dyslipidemia. The latter is characterized by a triad of hypertriglyceridemia, low plasma concentrations of high-density lipoproteins, and qualitative changes in LDLs. PCSK9 levels seem to correlate with many of these lipid parameters as well as with the insulin sensitivity indices, although the molecular mechanisms behind this association are still unknown or not completely elucidated. Nevertheless, this area of research represents an important starting point for a better understanding of the physiological role of PCSK9, also considering the recent approval of new therapies involving anti-PCSK9. Thus, in the present review, we will discuss the current knowledge on the role of PCSK9 in the context of MetS, alteration of lipids, glucose homeostasis, and inflammation.

Multiple microRNA regulation of lipoprotein lipase gene abolished by 3'UTR polymorphisms in a triglyceride-lowering haplotype harboring p.Ser474Ter.

BACKGROUND: Lipoprotein lipase (LPL) is a key enzyme in triglyceride (TG) metabolism. LPL gene single nucleotide polymorphisms (SNPs) are associated with TG concentrations however the functionality of many of these SNPs remains poorly understood. MicroRNAs (miR) exert post-transcriptional down-regulation and their target sequence on the 3'UTR may be altered by SNPs. We therefore investigated whether LPL 3'UTR SNPs could modulate plasma TG concentration through the alteration of miR binding-sites. METHODS AND RESULTS: We performed genetic association studies of LPL 3'UTR SNPs with TG concentrations in 271 type 2 diabetic patients and in general population samples (2997 individuals). A specific LPL haplotype (Hap4) was associated with lower plasma TG concentration (TG-0.18, IC95% [-0.30, -0.07] mmol/L or logTG-0.13, IC95% [-0.18, -0.08], p = 4.77·10(-8)) in the meta-analysis. Hap4 comprises seven 3'UTR SNP minor alleles and p.Ser474Ter (rs328) a well-documented nonsense mutation associated with low TG concentration although by an unknown mechanism so far. Bio-informatic studies identified several putative miRNA binding-sites on the wild-type Hap1 haplotype, lost on Hap4. Functional validation performed in HEK-293T cells using luciferase expression constructs with various LPL 3'UTR allele combinations demonstrated a binding of miR-29, miR-1277 and miR-410 on Hap1, lost on Hap4. This loss of specific miR binding-site in presence of Hap4 was independent of the allelic variation of p.Ser474Ter (rs328). CONCLUSIONS: We report the regulation of LPL by the miR-29, miR-1277 and miR-410 that is lost in presence of Hap4, a specific LPL TG-lowering haplotype. Consequently p.Ser474Ter association with TG concentration could be at least partially explained by its strong linkage disequilibrium with these functional 3'UTR SNPs.

Severe Hypertriglyceridemia due to a novel p.Q240H mutation in the Lipoprotein Lipase gene.

BACKGROUND: Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. FINDINGS: An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction. CONCLUSIONS: We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.

Primary hypertriglyceridemia in children and adolescents.

Primary disorders of lipid metabolism causing hypertriglyceridemia (HyperTG) result from genetic defects in triglyceride synthesis and metabolism. With the exception of lipoprotein lipase deficiency, these primary HyperTG disorders usually present in adulthood. However, some are unmasked earlier by precipitating factors, such as obesity and insulin resistance, and can be diagnosed in adolescence. Physical findings may be present and can include eruptive, palmer, or tuberoeruptive xanthomas. Triglyceride levels are very high to severe and can occur in the absence or the presence of other lipid abnormalities. Each of the causes of HyperTG is associated with an increased risk to develop recurrent pancreatitis and some may increase the risk of premature cardiovascular disease. Adoption of a healthy lifestyle that includes a low-fat diet, optimizing body weight, smoking avoidance/cessation, and daily physical activity is the first line of therapy. Pharmacologic therapies are available and can be beneficial in select disorders. Here, we review the causes of primary HyperTG in children and adolescents, discuss their clinical presentation and associated complications including the risk of pancreatitis and premature cardiovascular disease, and conclude with management and novel therapies currently in development. The goal of this article is to provide a useful resource for clinicians who may encounter primary HyperTG in the pediatric population.

JCL Roundtable: Hypertriglyceridemia due to defects in lipoprotein lipase function.

In this Roundtable, our intent is to discuss those rare genetic disorders that impair the function of lipoprotein lipase. These cause severe hypertriglyceridemia that appears in early childhood with Mendelian inheritance and usually with full penetrance in a recessive pattern. Dr Ira Goldberg from New York University School of Medicine and Dr Stephen Young from the University of California, Los Angeles have agreed to answer my questions about this topic. Both have done fundamental work in recent years that has markedly altered our views on lipoprotein lipase function. I am going to start by asking them to give us a brief history of this enzyme system as a clinical entity.

Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice.

OBJECTIVE: Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions. APPROACH AND RESULTS: Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways. CONCLUSIONS: Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

Biliverdin reductase isozymes in metabolism.

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets.

The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia.

PURPOSE OF REVIEW: To describe the roles of apolipoprotein C-III (apoC-III) and apoE in VLDL and LDL metabolism RECENT FINDINGS: ApoC-III can block clearance from the circulation of apolipoprotein B (apoB) lipoproteins, whereas apoE mediates their clearance. Normolipidemia is sustained by hepatic secretion of VLDL and IDL subspecies that contain both apoE and apoC-III (VLDL E+C-III+). Most of this VLDL E+C-III+ is speedily lipolyzed, reduced in apoC-III content, and cleared from the circulation as apoE containing dense VLDL, IDL, and light LDL. In contrast, in hypertriglyceridemia, most VLDL is secreted with apoC-III but without apoE, and so it is not cleared until it loses apoC-III during lipolysis to dense LDL. In normolipidemia, the liver also secretes IDL and large and medium-size LDL, whereas in hypertriglyceridemia, the liver secretes more dense LDL with and without apoC-III. These pathways establish the hypertriglyceridemic phenotype and link it metabolically to dense LDL. Dietary carbohydrate compared with unsaturated fat suppresses metabolic pathways mediated by apoE that are qualitatively similar to those suppressed in hypertriglyceridemia. SUMMARY: The opposing actions of apoC-III and apoE on subspecies of VLDL and LDL, and the direct secretion of LDL in several sizes, establish much of the basic structure of human apoB lipoprotein metabolism in normal and hypertriglyceridemic humans.

Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid ß-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for ß-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.

Organophosphate agents induce plasma hypertriglyceridemia in mouse via single or dual inhibition of the endocannabinoid hydrolyzing enzyme(s).

Diverse serine hydrolases including endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been suggested as secondary targets for organophosphate (OP) agents to exert adverse toxic effects such as lipid homeostasis disruption. The goal of this investigation is to verify that a major OP insecticide fenitrothion (FNT) induces plasma hypertriglyceridemia through the inhibition of FAAH and/or MAGL in comparison with that elicited by isopropyl dodecylfluorophosphonate (IDFP), a potent FAAH/MAGL inhibitor. Fasted mice were treated intraperitoneally with FNT or IDFP and were subsequently sacrificed for evaluations of plasma triglyceride (TG) levels and liver FAAH/MAGL activities. Plasma TG levels were significantly enhanced by the FNT or IDFP treatment (1.7- or 4.8-fold, respectively) compared with that of vehicle control. The IDFP exposure reduced the liver FAAH and MAGL activities, whereas the FNT exposure led to the preferential FAAH inhibition. The brain acetylcholinesterase was almost unaffected by the FNT or IDFP treatment, thus leading to no neurotoxic sign. Intriguingly, the TG elevations were averted by concomitant administration with the cannabinoid receptor antagonist AM251. The present findings suggest that OP agents induce plasma hypertriglyceridemia in mouse through single or dual inhibition of FAAH or/and MAGL, apparently leading to overstimulation of cannabinoid signal regulating energy metabolism.