Increased Plasma Triglyceride Research Articles

Targeting Lung-Gut Axis for Regulating Pollution Particle-Mediated Inflammation and Metabolic Disorders.

Cigarette smoking (CS) or ambient particulate matter (PM) exposure is a risk factor for metabolic disorders, such as insulin resistance (IR), increased plasma triglycerides, hyperglycemia, and diabetes mellitus (DM); it can also cause gut microbiota dysbiosis. In smokers with metabolic disorders, CS cessation decreases the risks of serious pulmonary events, inflammation, and metabolic disorder. This review included recent studies examining the mechanisms underlying the effects of CS and PM on gut microbiota dysbiosis and metabolic disorder development; one of the potential mechanisms is the disruption of the lung-gut axis, leading to gut microbiota dysbiosis, intestinal dysfunction, systemic inflammation, and metabolic disease. Short-chain fatty acids (SCFAs) are the primary metabolites of gut bacteria, which are derived from the fermentation of dietary fibers. They activate G-protein-coupled receptor (GPCR) signaling, suppress histone deacetylase (HDAC) activity, and inhibit inflammation, facilitating the maintenance of gut health and biofunction. The aforementioned gut microbiota dysbiosis reduces SCFA levels. Treatment targeting SCFA/GPCR signaling may alleviate air pollution-associated inflammation and metabolic disorders, which involve lung-gut axis disruption.

The Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio as a Risk Marker for Metabolic Syndrome and Cardiovascular Disease.

Atherosclerosis is an immunoinflammatory pathological procedure in which lipid plaques are formed in the vessel walls, partially or completely occluding the lumen, and is accountable for atherosclerotic cardiovascular disease (ASCVD). ACSVD consists of three components: coronary artery disease (CAD), peripheral vascular disease (PAD) and cerebrovascular disease (CCVD). A disturbed lipid metabolism and the subsequent dyslipidemia significantly contribute to the formation of plaques, with low-density lipoprotein cholesterol (LDL-C) being the main responsible factor. Nonetheless, even when LDL-C is well regulated, mainly with statin therapy, a residual risk for CVD still occurs, and it is attributable to the disturbances of other lipid components, namely triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Increased plasma TG and decreased HDL-C levels have been associated with metabolic syndrome (MetS) and CVD, and their ratio, TG/HDL-C, has been proposed as a novel biomarker for predicting the risk of both clinical entities. Under these terms, this review will present and discuss the current scientific and clinical data linking the TG/HDL-C ratio with the presence of MetS and CVD, including CAD, PAD and CCVD, in an effort to prove the value of the TG/HDL-C ratio as a valuable predictor for each aspect of CVD.

Palmitic Acid is Absorbed as sn-2 Monopalmitin from Milk and Formula with Rearranged Triacylglycerols and Results in Increased Plasma Triglyceride sn-2 and Cholesteryl Ester Palmitate in Piglets

Milk fatty acids contain 20–30% palmitic acid (16:0), with -70% of the 16:0 esterified to the sn-2 position of the milk triacylglycerol. Formulae containing vegetable and oleo oils contain different amounts of 16:0, but all have unsaturated fatty acids esterified to the triacylglycerol sn-2 position. Intraluminal triacylglycerol hydrolysis by endogenous lipases produces sn-2 monoacylglycerols and free fatty acids, which are absorbed and re-esterified in the enterocyte for secretion to plasma. The extent of absorption and re-esterification of sn-2 monoacylglycerols from milk or formula fats in infants is unknown. This was studied by feeding piglets sow milk or formulae containing similar total saturated fat, 18:1, 18:2(n-6) and 18:3(n-3) with unsaturated fatty acids at the sn-2 position or with rearranged triacylglycerols containing -30% 16:0, with 70% 16:0 in fatty acids at the sn-2 position. Feeding milk or 16:0 on the sn-2 position of formula with rearranged triacylglycerols resulted in higher 16:0 esterified to the plasma triacylglycerol sn-2 position and in cholesteryl esters than feeding formulae with 0.4 to 4.4% 16:0 in the sn-2 position fatty acids. The absorption of 16:0 as monopalmitin from milk and any metabolic importance in human infants has yet to be determined.

Hepatocyte mARC1 promotes fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with invitro and invivo studies of mARC1 knockdown. Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an invitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the invivo impacts of MTARC1. We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. Invitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and invivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown invitro and invivo. Collectively, our findings from human genetics, and invitro and invivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 forNAFLD.

Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4–45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

LOSS OF EPITHELIAL DUOX2 SIGNALING IS ACCOMPANIED BY A REDUCTION IN AKKERMANSIACEAE AND PROMOTES THE DEVELOPMENT OF METABOLIC SYNDROME IN A MICROBIOME-DEPENDENT MANNER

Abstract BACKGROUND Dysbiosis, an imbalance in microbial composition or function, is a key player in the development of conditions associated with chronic inflammation. The gut epithelium regulates host-microbiome dynamics through a variety of mechanisms, including the release of reactive oxygen species by NADPH oxidases. Dual oxidase 2 (DUOX2) is an antimicrobial NADPH oxidase expressed in the thyroid gland and gut epithelium and its activity is associated with dysbiosis. Loss of function mutations in DUOX2 are linked to the development of metabolic and inflammatory conditions such as congenital hypothyroidism and inflammatory bowel disease. Metabolic syndrome (MetS) is a cluster of conditions characterized by dysbiosis, inflammation, obesity, glucose intolerance, and hepatic steatosis. Dysbiosis in MetS is associated with a reduction in Bacteroidaceae and Akkermansiaceae. Despite this association, the mechanism by which dysbiosis leads to chronic inflammation and MetS is poorly defined. Here, we investigate the relationship between impaired epithelial barrier function and the development of MetS by focusing for the first time on intestinal specific DUOX2 deficiency as a mechanistic link. METHODS Mice carrying an intestinal epithelial-specific deletion of DUOX2 (DA IEC-KO), and wild-type (WT) littermates were fed a standard diet and euthanized at 24 weeks. DUOX2 activity was determined by Amplex Red. Metabolic alterations were determined by glucose tolerance tests and body, adipose tissue, and liver weight measurements and histological and gene expression assessments. Intestinal permeability was determined by FITC-dextran and microbial translocation assessments. The role of the microbiome was assessed by RNA-sequencing of stool and in antibiotic-treated mice. RESULTS DA IEC-KO mice produced less epithelial H2O2 and exhibited increased body, liver, and adipose tissue weights that were accompanied by glucose intolerance and increased plasma triglycerides, lipid deposition in the liver, and lipid droplet size in adipocytes. Expression of macrophage and thermogenesis markers, F4/80, CD68, and UCP1 were altered in the liver and adipose tissue of these mice. DA IEC-KO mice showed altered gut permeability and increased bacterial translocation to the liver and adipocytes. Microbial sequencing revealed that loss of intestinal epithelial DUOX2 activity led to significant differences in alpha and beta diversity, and a marked reduction in the family Akkermansiaceae. Antibiotic depletion of the microbiota abrogated all MetS phenotypes observed. CONCLUSION Our findings suggest that loss of intestinal epithelial DUOX2 activity leads to increased intestinal permeability and MetS in a microbiome dependent manner. These findings are significant in that they elucidate a novel role for epithelial DUOX2 at the host-microbial interface with distant systemic effects.

Effect of various dietary fructose concentrations on the gallstone formation process in mice.

Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds to biliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consuming diets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or 70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levels were analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only at very high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cholesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differences in the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8) no change in biliary lipid concentrations or in micellar and vesicular phospholipids. Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructose apparently does not alter the gallstone formation process in our experimental model.

M6A-Mediated PPARA Translational Suppression Contributes to Corticosterone-Induced Visceral Fat Deposition in Chickens.

Excess fat deposition in broilers leads to great economic losses and is harmful to consumers' health. Chronic stress in the life cycle of chickens could be an important trigger. However, the underlying mechanisms are still unclear. In this study, 30-day-old chickens were subcutaneously injected with 2 mg/kg corticosterone (CORT) twice a day for 14 days to simulate long-term stress. It was shown that chronic CORT exposure significantly increased plasma triglyceride concentrations and enlarged the adipocyte sizes in chickens. Meanwhile, chronic CORT administration significantly enlarged the adipocyte sizes, increased the protein contents of FASN and decreased HSL, ATGL, Beclin1 and PPARA protein levels. Moreover, global m6A methylations were significantly reduced and accompanied by downregulated METTL3 and YTHDF2 protein expression by CORT treatment. Interestingly, the significant differences of site-specific m6A demethylation were observed in exon7 of PPARA mRNA. Additionally, a mutation of the m6A site in the PPARA gene fused GFP and revealed that demethylated RRACH in PPARA CDS impaired protein translation in vitro. In conclusion, these results indicated that m6A-mediated PPARA translational suppression contributes to CORT-induced visceral fat deposition in chickens, which may provide a new target for the treatment of Cushing's syndrome.

Glucagon-like Peptide-2 Acutely Enhances Chylomicron Secretion in Humans Without Mobilizing Cytoplasmic Lipid Droplets.

A portion of ingested fats are retained in the intestine for many hours before they are mobilized and secreted in chylomicron (CM) particles. Factors such as glucagon-like peptide-2 (GLP-2) and glucose can mobilize these stored intestinal lipids and enhance CM secretion. We have recently demonstrated in rodents that GLP-2 acutely enhances CM secretion by mechanisms that do not involve the canonical CM synthetic assembly and secretory pathways. To further investigate the mechanism of GLP-2's potent intestinal lipid mobilizing effect, we examined intracellular cytoplasmic lipid droplets (CLDs) in intestinal biopsies of humans administered GLP-2 or placebo. A single dose of placebo or GLP-2 was administered subcutaneously 5 hours after ingesting a high-fat bolus. In 1 subset of participants, plasma samples were collected to quantify lipid and lipoprotein concentrations for 3 hours after placebo or GLP-2. In another subset, a duodenal biopsy was obtained 1-hour after placebo or GLP-2 administration for transmission electron microscopy and proteomic analysis. GLP-2 significantly increased plasma triglycerides by 46% (P = 0.009), mainly in CM-sized particles by 133% (P = 0.003), without reducing duodenal CLD size or number. Several proteins of interest were identified that require further investigation to elucidate their potential role in GLP-2-mediated CM secretion. Unlike glucose that mobilizes enterocyte CLDs and enhances CM secretion, GLP-2 acutely increased plasma CMs without significant mobilization of CLDs, supporting our previous findings that GLP-2 does not act directly on enterocytes to enhance CM secretion and most likely mobilizes secreted CMs in the lamina propria and lymphatics.

Polygenic risk in Type III hyperlipidaemia and risk of cardiovascular disease: An epidemiological study in UK Biobank and Oxford Biobank

BackgroundType III hyperlipidaemia (T3HL) is characterised by equimolar increases in plasma triglycerides (TG) and cholesterol in <10% of APOE22 carriers conveying high cardiovascular disease (CVD) risk. We investigate the role of a weighted triglyceride-raising polygenic score (TG.PS) precipitating T3HL. MethodsThe TG.PS (restricted to genome-wide significance and weighted by published independent effect estimates) was applied to the Oxford Biobank (OBB, n = 6952) and the UK Biobank (UKB, n = 460,037), to analyse effects on plasma lipid phenotypes. Fasting plasma lipid, lipoprotein biochemistry and NMR lipoprotein profiles were analysed in OBB. CVD prevalence/incidence was examined in UKB. ResultsOne TG.PS standard-deviation (SD) was associated with 13.0% (95% confidence-interval 12.0–14.0%) greater TG in OBB and 15.2% (15.0–15.4%) in UKB. APOE22 carriers had 19.0% (1.0–39.0%) greater TG in UKB. Males were more susceptible to TG.PS effects (4.0% (2.0–6.0%) greater TG with 1 TG.PS SD in OBB, 1.6% (1.3–1.9%) in UKB) than females. There was no interaction between APOE22 and TG.PS, BMI, sex or age on TG. APOE22 carriers had lower apolipoprotein B (apoB) (OBB; −0.35 (−0.29 to −0.40)g/L, UKB; −0.41 (−0.405 to −0.42)g/L). NMR lipoprotein lipid concentrations were discordant to conventional biochemistry in APOE22 carriers.In APOE22 compared with APOE33, CVD was no more prevalent in similarly hypertriglyceridaemic participants (OR 0.97 95%CI 0.76–1.25), but was less prevalent in normolipidaemia (OR 0.81, 95%CI 0.69–0.95); no differences were observed in CVD incidence. ConclusionsTG.PS confers an additive risk for developing T3HL, that is of comparable effect size to conventional risk factors. The protective effect of APOE22 for prevalent CVD is consistent with lower apoB in APOE22 carriers.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Abstract 12042: A Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac LDLR Expression

Background: HFpEF prevalence has surpassed that of HFrEF. Elevated accumulation of myocardial lipids is a prominent feature of HFpEF patients and the gene for lipoprotein lipase (LPL) in cardiac biopsies is decreased compared with HFrEF or healthy controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and increasing plasma triglycerides (TG) and LDL cholesterol. We hypothesized that hyperlipidemia driven by p407 and overexpression (OE) of cardiac LDLR in mice mimics a subset of human HFpEF. Methods: WT-129 mice were subject to 4 wks of biweekly i.p. p407-injections with or without a single i.v. injection of AAV9-cTnT-LDLR (n=31); AAV9-cTnT-Luciferase control (n=11), or single i.v. injection with AAV9-cTnT-LDLR alone (n=10). Treatment groups were compared to an untreated group (n=26). Echo, blood pressure (BP), whole-body plethysmography (WBP), ECG telemetry, activity wheel monitoring (AWM), biochemical tests, and histological changes were assessed at 4-8 wks. Results: At 4 wks, p407 and LDLR OE led to diastolic dysfunction (DD) (prolonged IVRT, decreased E/A (p&lt;0.05 and p&lt;0.001 respectively)), preserved EF and increased LV wall thickness (LVID and LVAW, p&lt;0.0001). BP and WBP were normal at 4 wks but respiration (breaths per minute) decreased at 8 wks (p&lt;0.01). ECG and AWM respectively indicated heart block and decreased exercise activity (p&lt;0.001). With the double treatment, total cholesterol increased in heart, skeletal muscle and liver (p&lt;0.05), while TG was decreased only in hearts (p&lt;0.001) and liver (p&lt;0.05). Double treatment also promoted elevated myocardial lipids, fibrosis, increased Wet/Dry lung (p&lt;0.001) and HW/BW (p&lt;0.05). Xanthelasma, ascites, and cardiac ischemia were noted in the double and single, p407 + luciferase groups. Sudden death (SD) occurred between 6-12 wks in double and p407+Luciferase treatment groups. Conclusion: We present a unique model of early onset, rapidly evolving HFpEF where double treatment mice acquire DD, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved EF in the absence of obesity, HTN, CKD or DM. The model may represent a subset of HFpEF wherein hyperlipidemia drives a severe phenotype with SD as a prominent endpoint.

Overexpression of VEGF-B alters cardiac lipid metabolism and predisposes to heart failure

Abstract Background The compensatory phase of left ventricular hypertrophy (LVH) is characterised by sufficient mitochondrial density and energy production, but prolonged stress leads to cardiac decompensation and decreased mitochondrial biogenesis. This results in energy deficiency and compromised contractile ability, eventually leading to heart failure (HF). Vascular endothelial growth factor B (VEGF-B) is a potent inducer of cardiac angiogenesis and LVH, and more recently it has been associated with lipid metabolism and cardiac function. However, its exact role in these processes has remained unresolved. Purpose We wanted to elucidate the effects of VEGF-B overexpression on cardiac metabolism and the development of LVH and HF. Methods We used mice expressing VEGF-B transgene under cardiac-specific MHCα promoter and induced pressure overload with angiotensin II infusion. We monitored the cardiac function with high-resolution transthoracic echocardiography and performed immunohistochemical analyses to assess the level of cardiac fibrosis. Furthermore, we analyzed cardiac lipid metabolism with non-targeted LC-MS metabolite profiling and performed functional 3H -labelled triolein uptake studies combined with quantitative RT-PCR. Results In this study, we show that the cardiac-specific overexpression of VEGF-B leads to increased plasma triglyceride and free fatty acid levels but reduced cardiac lipid accumulation. Non-targeted LC-MS profiling analysis revealed that the level of cardiac glycerolipids and glycerophospholipids were significantly downregulated although changes in cardiac lipid uptake on functional or gene expression level were not detected. To assess how these metabolic changes affect the development of LVH and HF, we subjected MHCα-VEGF-B mice to angiotensin II infusion. Surprisingly, the survival of MHCα-VEGF-B mice dramatically started to decline after four days of angiotensin II infusion and was only 30% at the 14-day time point. Echocardiographic measurements revealed that the MHCα-VEGF-B mice developed severe HF seen as reduced ejection fraction when compared to control mice (32.2% vs. 64.2% respectively), significantly increased LV end-diastolic diameter and LV volume when compared to the controls. VEGF-B overexpression during pressure overload resulted in severe cardiac fibrosis and downregulation of genes responsible for lipid and glucose uptake, metabolic regulation and mitochondrial function indicating severe cardiac energy deficit. Interestingly, a high fat diet feeding prevented the development of HFrEF by 100% and the suppression of all metabolic pathways. Conclusion VEGF-B regulates cardiac energy production and the overexpression of VEGF-B results in cardiac energy deficit that during pressure overload leads to HFrEF and severe mortality. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC and H2020

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia

ObjectiveGlycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a “glycerol shunt”, a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. MethodsWe generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. ResultsLKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. ConclusionsThe glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.

Apolipoprotein A5 gene polymorphism (rs662799) and cardiovascular disease in end-stage kidney disease patients

BackgroundPlasma triglyceride (TG) levels are a significant risk factor for cardiovascular disease (CVD). The APOA5 gene is one of the crucial factors in plasma TG metabolism regulation. The rs662799 polymorphism in the APOA5 gene has been reported to be associated with cardiovascular disease. The goal of this study was to evaluate the potential association of this variant with CVD in patients with end-stage kidney disease. MethodsIn this case–control study the polymorphism was analyzed using the PCR–RFLP method in 800 consecutive patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared between subgroups of patients with CVD (552) versus those without CVD (248).ResultsThe frequency of the minor allele (C) in the healthy individuals was 9% compared to 12% in ESRD group (p = 0.09). The difference between groups was slightly higher for CC homozygote (3.5% versus 1.6%, p = 0.042). The ESKD patient group was analyzed according to the presence or absence of CVD. The significant differences in the polymorphism distribution were revealed in this analysis. The frequency of the C allele in the CVD + subgroup was 14% compared to 6% in CVD- patients (p = 0.001). In the CVD + subgroup the ORs (95% CI) for the C allele and CC genotype were 2.41 (1.61–3.6), p < 0.001 and 3.13 (1.07–9.14), p = 0.036, respectively. This indicates to the association of the variant C allele with cardiovascular disease in ESKD patients. The CC homozygotes have a threefold higher odds of CVD compared to TT homozygotes. The highest frequency of the C allele (18%) was observed in subgroup of patients with diabetic nephropathy, with OR (95% CI) 3.40 (2.13–5.43), p < 0.001.The presence of minor allele (CC and CT genotypes) was significantly associated with increased plasma triglyceride levels (p < 0.001 for both CVD + and CVD- groups).ConclusionThe present study demonstrated the effect of rs662799 polymorphism on plasma TG levels and its association with the development of cardiovascular disease in ESKD patients.

Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon.

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels that can exceed 22.58 mmol/l. The disease is associated with recurrent episodes of abdominal pain and pancreatitis, eruptive cutaneous xanthomatosis, lipemia retinalis, and hepatosplenomegaly. A consanguineous Syrian family who migrated to Lebanon was referred to our laboratory after perceiving familial chylomicronemia syndrome in two children. The LPL and PCSK9 genes were sequenced and plasma PCSK9 levels were measured. Sanger sequencing of the LPL gene revealed the presence of the p.(Val227Phe) pathogenic variant in exon 5 at the homozygous state in the two affected children, and at the heterozygous state in the other recruited family members. Interestingly, PCSK9 levels in homozygous carriers of the p.(Val227Phe) were ≈50% lower than those in heterozygous carriers of the variant (p-value = 0.13) and ranged between the 5th and the 7.5th percentile of PCSK9 levels in a sample of Lebanese children of approximately the same age group. Moreover, this is the first reported case of individuals carrying simultaneously an LPL pathogenic variant and PCSK9 variants, the L10 and L11 leucine insertion, which can lower and raise low-density lipoprotein cholesterol (LDL-C) levels respectively. TG levels fluctuated concomitantly between the two children, were especially high following the migration from a country to another, and were reduced under a low-fat diet. This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of familial hyperchylomicronemia.

Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine.

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.

Increasing angiotensin-converting enzyme 1 regulated by histone 3 lysine 27 hyperacetylation in high-fat diet-induced hypertensive rat kidney.

Obesity is a key risk factor of hypertension. Angiotensin-converting enzyme 1 (ACE1) is a key enzyme involved in the renin-angiotensin-aldosterone system (RAAS), which contributes to obesity-related hypertension (OrHTN). Emerging evidence has shown that histone acetylation is also involved in OrHTN. As kidney is an effector organ that activates the RAAS by secreting renin after hypertension occurs, this study aimed to explore the regulatory role of histone acetylation on renal RAAS expression. Nineteen male Wistar rats were randomly divided into a control group ( n = 9, fed normal chow) and a high-fat diet (HFD) group ( n = 10, fed HFD for 16 weeks). The renal transcriptome and histone acetylation spectrum was analyzed by RNA sequencing and tandem mass spectrometry and was further confirmed by RT-qPCR, western blot, and immunohistochemistry. Then, chromatin immunoprecipitation (ChIP)-qPCR analysis was performed for the detection of DNA-protein interaction. After 16-week HFD, the rats became obese with increased plasma triglyceride and high blood pressure. Increased ACE1 and histone 3 lysine 27 acetylation (H3K27ac) expression levels were found in OrHTN rat kidneys. The following ChIP-qPCR analysis illustrated that the upregulation of ACE1 transcription was mediated by increased H3K27ac. H3K27ac could be an important histone acetylation site that activates renal ACE1 in HFD-induced hypertensive rats.

Impact of the duration of program hemodialysis and heart failure on the pattern of lipid profile in patients with end-stage chronic kidney disease

Background and Aims : Patients with chronic kidney disease often have multiple comorbidities and the high cardiovascular mortality. Dyslipidemia is one of the possible risk factors associated with uremia and an increased risk of cardiovascular disease. The aim of our study was to evaluate the influence of the duration of program hemodialysis and presence of heart failure (HF) in patients with end-stage chronic kidney disease on the pattern of lipid profile.Methods: All patients were divided into groups: I group included 20 patients with end-stage chronic kidney disease (ESCKD) on hemodialysis (duration - 5 years),II group - 20 patients with ESCKD (over 10 years), III group - 16 patients with ESCKD on hemodialysis with HF (over 10 years). Control group – 12 healthy persons. Laboratory blood tests of lipid profile (Triglycerides (TG), Total Cholesterol, High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL)), C Reactive Protein (CRP) were analyzed in addition to standard diagnostic program.Results: The pattern of lipid profile is characterized by increased plasma TG (p˂0.05) second and third groups due to elevated VLDL and decreased HDL compared to the control group. There were a significant difference (p˂0.05) in patients of the first and the third groups between of the lipid profile. We observed positive correlation of dyslipidemia with CRP (p˂0.05). Dyslipidemia is associated with uremia.Conclusions: ESCKD patients have increased risk of CVD. A higher prevalence of dyslipidemia is common among patients with ESCKD on the program hemodialysis. HF is associated with lipoprotein abnormalities and cardiovascular mortality. Background and Aims : Patients with chronic kidney disease often have multiple comorbidities and the high cardiovascular mortality. Dyslipidemia is one of the possible risk factors associated with uremia and an increased risk of cardiovascular disease. The aim of our study was to evaluate the influence of the duration of program hemodialysis and presence of heart failure (HF) in patients with end-stage chronic kidney disease on the pattern of lipid profile. Methods: All patients were divided into groups: I group included 20 patients with end-stage chronic kidney disease (ESCKD) on hemodialysis (duration - 5 years),II group - 20 patients with ESCKD (over 10 years), III group - 16 patients with ESCKD on hemodialysis with HF (over 10 years). Control group – 12 healthy persons. Laboratory blood tests of lipid profile (Triglycerides (TG), Total Cholesterol, High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL)), C Reactive Protein (CRP) were analyzed in addition to standard diagnostic program. Results: The pattern of lipid profile is characterized by increased plasma TG (p˂0.05) second and third groups due to elevated VLDL and decreased HDL compared to the control group. There were a significant difference (p˂0.05) in patients of the first and the third groups between of the lipid profile. We observed positive correlation of dyslipidemia with CRP (p˂0.05). Dyslipidemia is associated with uremia. Conclusions: ESCKD patients have increased risk of CVD. A higher prevalence of dyslipidemia is common among patients with ESCKD on the program hemodialysis. HF is associated with lipoprotein abnormalities and cardiovascular mortality.

A novel missense variant in CREB3L3 gene associated with severe hypertriglyceridemia

Background and Aims : Severe hypertriglyceridemia (HTG) is a rare disease consisting in increased plasma triglyceride (TG) levels (>10 mmol/L). Patients can show eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly and pancreatitis. For long time five genes were considered causative of the disease with autosomal recessive inheritance: Lipoprotein lipase (LPL), Apolipoprotein A-V (APOA5), Apolipoprotein C-II (APOC2), Glycosyl-phosphatidyl-inositol-anchored HDL-binding protein (GPIHBP1) and Lipase maturation factor-1 (LMF1).