Elevated Plasma Triglyceride Research Articles

Ursane-type triterpene oligoglycosides with anti-hepatosteatosis and anti-hyperlipidemic activity from the leaves of Ilex paraguariensis A. St.-Hil.

The methanol extract from the leaves of Ilex paraguariensis A. St.-Hil. (Aquifoliaceae), popularly known as mate, maté, or yerba maté, inhibits the intracellular triglyceride accumulation in HepG2 cells and suppresses the plasma triglyceride elevation in olive oil-treated mice. Three new triterpene saponins, termed mateosides I (1), II (2), and III (3), were isolated from the extract along with 29 known compounds. The structures of 1-3 were elucidated based on chemical and spectroscopic evidence. Among the isolates, principal saponin constituents, 2 and matesaponins 1 (7) and 2 (9), potently inhibited the triglyceride accumulation in HepG2 cells simultaneously treated with oleic acid and high glucose. In vivo assay of the methanol extract of I. paraguariensis revealed that 7 and 9 showed anti-hyperlipidemic activities in olive oil-treated mice. These results suggested that the saponin constituents of I. paraguariensis could be valuable bioactive marker for the anti-obesogenic activity.

Abstract P206: Proteomic And Metabolomic Signatures Of Plasma Triglyceride-related Trait Responses To Regular Exercise

Introduction: Elevated plasma triglycerides (TG) are associated with risk of cardiovascular disease and are modifiable through lifestyle interventions such as regular exercise. However, TG responses to regular exercise are characterized by significant inter-individual differences. Hypothesis: We hypothesized that baseline levels of circulating proteins and metabolites are associated with TG response to exercise and can predict exercise-induced changes in plasma TG traits. Methods: We measured circulating proteins (n=4979 proteins) and metabolites (n=300) in 650 Black and White adults of the HERITAGE Family Study who completed 20 weeks of exercise training and had complete data on TG traits. We investigated two TG-related traits that significantly improved with training: fasting TG and large TG-rich lipoprotein particle concentration (LTRLP). The association between baseline analyte values and exercise-induced changes in TG traits were examined using linear mixed models adjusted for age, sex, race, BMI, baseline trait value, and the random effect of family membership. Significance was determined as FDR<0.05. Molecular signatures of TG trait responses were generated via elastic net regression tuned using leave-one-out cross validation. Results: Regular exercise significantly reduced plasma TG (-1.03±1.3 mmol/L, p=0.01) and LTRLP (-0.24±2.2 nmol/L, p= 0.007), with their training-induced changes moderately correlated (r=0.4, p<0.0001). We identified largely distinct panels of baseline analytes associated with changes in TG and LTRLP ( Table 1 ). Similarly, elastic net regression yielded distinct models of 99 analytes for TG and 315 analytes for LTRLP responses to exercise with accuracy of RMSE=1.28 mmol/L for TG and 2.16 nmol/L for the LTRLP model. Conclusions: We identified panels of proteins and metabolites associated with exercise-induced changes in TG traits and demonstrate, within our data, circulating analytes hold promise for predicting the exercise responsiveness of plasma TG-related traits.

A Tale of Two New Targets for Hypertriglyceridaemia: Which Choice of Therapy?

Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are novel metabolic targets for correcting hypertriglyceridaemia (HTG). As a background to their potential clinical use, we review the metabolic aetiology of HTG, particular abnormalities in triglyceride-rich lipoproteins (TRLs) and their role in atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Molecular and cardiometabolic aspects of ANGPTL3 and apoC-III, as well as inhibition of these targets with monoclonal antibody and nucleic acid therapies, are summarized as background information to descriptions and analyses of recent clinical trials. These studies suggest that ANGPTL3 and apoC-III inhibitors are equally potent in lowering elevated plasma triglycerides and TRLs across a wide range of concentrations, with possibly greater efficacy with inhibition of apoC-III. ANGPTL3 inhibition may, however, have the advantage of greater lowering of plasma LDL cholesterol and could specifically address elevated LDL cholesterol in familial hypercholesterolaemia refractory to standard drug therapies. Large clinical outcome trials in relevant populations are still required to confirm the long-term efficacy, safety and cost effectiveness of these potent agents for mitigating the complications of HTG. Beyond targeting severe chylomicronaemia in the prevention of acute pancreatitis, both agents could be useful in addressing residual risk of ASCVD due to TRLs in patients receiving best standard of care, including behavioural modifications, statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 inhibitors.

Rubicon deficiency exacerbates fasting-induced hepatic steatosis

Abstract Objective: Rubicon is an inhibitory interacting protein of the autophagy-related protein Uvrag. We previously showed that Rubicon deficiency promotes autophagic flux in vivo and that autophagy can degrade lipid droplets. This study aimed to investigate the effects of Rubicon deficiency on fasting-induced hepatic steatosis. Methods: Two-month-old wild-type (WT) and Rubicon-deficient mice were subjected to feeding or fasting for 24 hours to induce hepatic steatosis. The distribution of liver lipid droplets was revealed by oil red O staining. Hepatic and plasma triglyceride, non-esterified fatty acid (NEFA), and cholesterol levels were detected using commercially available kits. Real-time reverse transcriptase-polymerase chain reaction was performed to analyze the mRNA expression of genes related to lipid metabolism in the liver. Western blot was conducted to assess autophagy-related protein levels in the liver. The animal experiments were approved by the Institutional Animal Care and Use Committee at Shanghai Jiao Tong University, China. Results: We showed that under fasting conditions, Rubicon-deficient mice had more lipid droplets in the liver than WT controls. Consistent with these results, the hepatic triglyceride, NEFA, and cholesterol levels in fasted Rubicon-deficient mice were significantly higher than those of fasted WT controls. The levels of SREBP-1, a key regulator of lipid synthesis, were significantly lower in livers from fasted WT mice than those of fed WT mice. However, the decrease in SREBP-1 in fasted mice was attenuated by Rubicon deficiency. Western blot analysis demonstrated that the fasting-induced increase in autophagic flux was amplified by Rubicon deficiency. Finally, we showed that Rubicon deficiency in mice led to elevated plasma triglyceride and NEFA acid levels under fasting conditions. Conclusion: Rubicon deficiency exacerbates fasting-induced hepatic steatosis in mice.

The Role of Fructose as a Cardiovascular Risk Factor: An Update.

There is increasing presence of fructose in food and drinks, and some evidence suggests that its higher consumption increases cardiovascular risk, although the mechanisms still remain not fully elucidated. Cardiovascular diseases (CVD) are still responsible for one-third of deaths worldwide, and therefore, their prevention should be assessed and managed comprehensively and not by the evaluation of individual risk factor components. Lifestyle risk factors for CVD include low degree of physical activity, high body mass index, alcohol consumption, smoking, and nutritional factors. Indeed, nutritional risk factors for CVD include unhealthy dietary behaviors, such as high intake of refined foods, unhealthy fats, added sugars, and sodium and a low intake of fruits, vegetables, whole grains, fiber, fish, and nuts. Even though there is no definitive association between CVD incidence and high consumption of total sugar, such as sucrose and fructose, there is, however, evidence that total sugars, added sugars, and fructose are harmfully associated with CVD mortality. Since high fructose intake is associated with elevated plasma triglyceride levels, as well as insulin resistance, diabetes hyperuricemia, and non-alcoholic fatty liver disease, further longitudinal studies should be conducted to fully elucidate the potential association between certain sugars and CVD.

Prevalence of Dyslipidemia in Patients With Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Introduction: Diabetes mellitus (DM), a chronic metabolic noncommunicable disease (NCD), has assumed epidemic proportions worldwide. Type 2 diabetes (T2D) is defined as chronic high blood glucose levels due to the deficiency of insulin or resistance to it. Dyslipidemia is one of the major causes of cardiovascular diseases in patients with T2D. It is characterized by elevated plasma triglyceride (TG), low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol, which is mostly present in patients with DM.Methods: We conducted a retrospective cross-sectional study at the King Faisal University (KFU) Health Center in the eastern region of Saudi Arabia. The data of patients from October 2014 to February 2021 were collected. We collected the patients’ data from the KFU Health Center after obtaining approval from the KFU polyclinic administration. Prior ethical approval was taken from the Institutional Review Board of Ethics and Research Committee in the College of Medicine, KFU (approval number, 2020-10-62). We collected patients’ data, including their gender, age, nationality, and blood analysis (lipids profile - TGs, HDL, LDL, and hemoglobin A1c [HbA1c] levels).Result: This study included 191 patients with T2D, 137 (71.7%) were from Saudi Arabia, and 54 (28.3%) were from other countries. Patients’ age ranged from 21 to 100 years, with a mean age of 56.2 ± 11.8 years. There were 107 (56%) females. Cholesterol levels ranged from 102 to 300 mg/dl with a mean value of 187.3 mg/dl.Conclusion: In the current study, we assessed the association between HbA1c levels and lipid profiles in patients with T2D at the KFU Health Center in the eastern region of the Kingdom of Saudi Arabia. Our results on the adjusted relationship of HbA1c with lipid profile through regression model have demonstrated that HDL alone had significant adjusted relation with HbA1c if other factors are kept constant. We suggest focusing on TC and HDL levels in T2D health management in future studies.

Perivascular adipose tissue-derived nitric oxide compensates endothelial dysfunction in aged pre-atherosclerotic apolipoprotein E-deficient rats

Background and aimsAtherosclerosis is a major contributor to global mortality and is accompanied by vascular inflammation and endothelial dysfunction. Perivascular adipose tissue (PVAT) is an established regulator of vascular function with emerging implications in atherosclerosis. We investigated the modulation of aortic relaxation by PVAT in aged rats with apolipoprotein E deficiency (ApoE−/−) fed a high-fat diet as a model of early atherosclerosis. Methods and resultsApoE−/− rats (N = 7) and wild-type Sprague-Dawley controls (ApoE+/+, N = 8) received high-fat diet for 51 weeks. Hyperlipidemia was confirmed in ApoE−/− rats by elevated plasma cholesterol (p < 0.001) and triglyceride (p = 0.025) levels. Early atherosclerosis was supported by increased intima/media thickness ratio (p < 0.01) and ED1-positive macrophage influx in ApoE−/− aortic intima (p < 0.001). Inflammation in ApoE−/− PVAT was characteristic by an increased [18F]FDG uptake (p < 0.01), ED1-positive macrophage influx (p = 0.0003), mRNA expression levels of CD68 (p < 0.001) and IL-1β (p < 0.01), and upregulated iNOS protein (p = 0.011). The mRNAs of MCP-1, IL-6 and adiponectin remained unchanged in PVAT. Aortic PVAT volume measured with micro-PET/CT was increased in ApoE−/− rats (p < 0.01). Maximal endothelium-dependent relaxation (EDR) to acetylcholine in ApoE−/− aortic rings without PVAT was severely impaired (p = 0.012) compared with controls, while ApoE−/− aortic rings with PVAT showed higher EDR than controls. All EDR responses were blocked by L-NMMA and the expression of eNOS mRNA was increased in ApoE−/− PVAT (p = 0.035). ConclusionUsing a rat ApoE−/− model of early atherosclerosis, we capture a novel mechanism by which inflammatory PVAT compensates severe endothelial dysfunction by contributing NO upon cholinergic stimulation.

Abstract 13168: Total Lipoprotein Lipase Deficiency Does Not Impact Atherosclerosis Development in Low Density Lipoprotein Receptor Deficient Mice

Introduction: Elevated LDL cholesterol (LDL-C) is a major causal factor for CVD. However, the importance of elevated triglyceride rich lipoproteins (TRLs) on CVD is still being investigated. Lipoprotein lipase (LpL) is the rate limiting enzyme hydrolyzing circulating very low density lipoprotein (VLDL) and chylomicrons. The effect of increased TRLs as an independent factor on atherosclerosis is not known, in part, because hypertriglyceridemia associates with low levels of LDL-C. Objective: We tested whether whole body LpL deficiency in mice combined with LDL receptor (LDLR) deficiency and an atherogenic diet affects lesion formation. Hypothesis: LpL deficient mice will not show increased atherosclerosis progression as compared to control mice, despite severe dyslipidemia, due to reduced infiltration of atherogenic lipids into the aortic endothelium. Methods: Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injection to activate beta actin-driven cre. To knock down hepatic LDLR we utilized anti sense oligonucleotides (ASOs) as well as a PCSK9 expressing AAV. Results: i Lpl -/- mice on chow diet have elevated plasma triglycerides, increased VLDL cholesterol, lower LDL-C and lower high density lipoprotein cholesterol (HDL-C) compared to control Lpl fl/fl mice. However, when hepatic LDLR was knocked down with using LDLR ASO or AAV PCSK9, iLpl -/- mice displayed elevated LDL-C of about 150 mg/dl, similar to the levels seen in control mice with LDLR knockdown. When i Lpl -/- mice were fed an atherogenic Western diet for 16 weeks, i Lpl -/- mice developed severe hypertriglyceridemia (1500-8000 mg/dl) and increased total cholesterol to ~1500 mg/dl. LDL-C levels were similar to those of control mice with LDLR knockdown; ~200 mg/dl. HDL-C was lower in i Lpl -/- mice compared to the controls (~10 mg/dl vs ~30 mg/dl). i Lpl -/- mice had slightly smaller lesions in brachiocephalic arteries but macrophage content was similar to the controls. Aortic root lesion size was similar in both groups of mice. Conclusion: Despite severe hypertriglyceridemia, hypercholesterolemia and low HDL-C, iLpL -/- mice did not exhibit altered atherosclerosis progression, likely because of the absence of LpL-derived atherogenic lipids or remnant lipoproteins.

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Familial combined hyperlipidemia is a polygenic trait.

: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified. : Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs. : Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.

Plasma lipemia: When the blood donor becomes a patient

Lipemic plasma donations are not a strange phenomenon to blood bankers. According to quality standards for plasma fractionation, lipemic plasma donations must be discarded. Beyond quality control and inventory aspects, plasma lipemia is also an important risk factor for cardiovascular diseases, acute pancreatitis and is associated with overall mortality, however little attention is given to the management of these donors in the literature.A retrospective analysis of every whole blood donation that yielded lipemic plasma between January 1st 2018 and December 31st 2019 was made. The medical examination and donor history for the respective donation was reviewed and the available data was collected regarding hour of donation, gender, age, drugs and coexisting pathologies. Whether the donor was called back for a follow up evaluation regarding the lipemic plasma was also noted.Our blood center received 18274 whole blood donations of which 115 (0,63 %) were reported as having plasma lipemia, in the period of this study. Of these 115 donors, 103 (89,57 %) were male. The average age was 47,63 ± 10,65 years. A clear peak in lipemic plasma donations 4 hours after the classic lunch hours is visible. For 88,70 % of the donors, this was the first time their hypertriglyceridemia was identified.The nonfasting elevation of plasma triglycerides in these donors represents a true metabolic derangement. This is a golden opportunity for early intervention and follow up evaluation is indicated. More attention must be given during the medical evaluation to properly identify donors at risk of lipemic donations.

Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) accounts for 90–95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160−190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17β-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.

Abstract 121: Exploiting Natural Genetic Variation In The Human Triglyceride Regulator APOA5 To Understand Its Function

Plasma triglycerides (TGs) are an independent predictor of the risk for CAD, the leading cause of death worldwide. TGs are also positively associated with risk and severity of hyperTG-induced acute pancreatitis (HTG-AP). Current therapies are often insufficient in reducing extremely elevated TGs. We believe that apolipoprotein A-V (apoA-V, encoded by APOA5) can fill this unmet medical need. ApoA-V is a potent modulator of TG metabolism; it enhances lipoprotein lipase TG hydrolysis. We hypothesize that naturally occurring human APOA5 variants can inform ApoA-V function and identify novel ApoA-V based therapeutic axes. We used the Penn Medicine Biobank (PMBB) to identify and measure plasma TGs of carriers of APOA5 variants predicted to change ApoA-V structure-function. Then, we used hydrogen-deuterium exchange mass spectroscopy to determine the secondary structure of ApoA-V, thereby identifying putative functional domains onto which we mapped our variants of interest. Finally, we characterized the plasma lipid effects of these mutants using adeno-associated viral (AAV) vectors in apoa5 knockout (KO) mice. We identified APOA5 variants associated with changes in plasma TGs. These variants primarily fall near the central heparin binding domain or C-terminal lipid binding domain. We selected APOA5 Q275X, which removes the entire lipid binding domain, for further interrogation. Apoa5 KO mice that received APOA5 Q275X AAV had higher plasma TGs than mice treated with WT APOA5 AAV. While WT ApoA-V protein associated with VLDL and HDL particles, Q275X ApoA-V protein appeared in lipoprotein free fractions. We have identified APOA5 variants associated with plasma TG phenotypes in humans, and mapped them to an experimentally determined ApoA-V secondary structure to identify the functional domains likely impacted. We have identified APOA5 Q275X as a loss of function variant that fails to bind lipoprotein particles and is associated with elevated plasma TGs. Continued study of this and other interesting naturally occurring variants will provide insight into the function of ApoA-V in TG metabolism. These insights can help us to therapeutically enhance ApoA-V to rapidly reduce TG levels during acute HTG-AP and to help prevent recurrent HTG-AP.

A spontaneously hypertensive diet-induced atherosclerosis-prone mouse model of metabolic syndrome

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.

Exploring the role of ATP10A in diet‐induced obesity, insulin resistance, and type 2 diabetes

Type IV P-type ATPases (P4-ATPases) are enzymes that catalyze the translocation of lipids across plasma membranes. Our lab recently discovered that Atp10a, a mammalian P4-ATPase, can translocate glucosylceramide, a sphingolipid. Both Atp10a and glucosylceramide have been independently implicated in metabolic dysfunction. To explore the role of Atp10a in metabolic dysfunction and sphingolipid metabolism, we created a novel Atp10a knockout (KO) mouse model. Atp10a KO mice display a female-specific excess weight gain on standard chow that is exacerbated by 12 weeks of high fat feeding and this is attributable to increased adiposity. Additionally, they display an accumulation of neutral lipids and altered ceramide metabolism in their livers. After a 5 hour fast, these mice exhibit elevated blood glucose levels that are not coupled to a proportional elevation in insulin levels. Atp10a KO mice also exhibit elevated plasma free fatty acids, cholesterol, and triglycerides. Thus far, our studies have shown that knocking out Atp10a in a mouse results in sex-specific perturbations to body weight and composition, glucose homeostasis, plasma lipid levels, and liver metabolism.

Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

URIC ACID-ASSOCIATED CARDIAC TISSUE DAMAGE CAUSED BY HIGH FAT DIET IS REVERSED BY SODIUM BUTYRATE

Objective: Increased global consumption of high-fat/high-calorie diet has led to higher incidence of the multifactorial cardiometabolic syndrome especially among women. The links between glucose deregulation and eventual mortal cardiac diseases are still being investigated. However, several reports have implicated elevated uric acid (UA) in the progression of metabolic disorders especially during high-fructose diet. Also, butyrate (BUT) a short-chain fatty acid is being identified with intriguing therapeutic potentials in metabolic disorders. We therefore hypothesized that high-fat diet-induced glucose deregulation and cardiac tissue damage are associated with elevated UA and attenuated by BUT in female rats. Design and method: Twenty-four 10-week-old female Wistar rats with weights ranging from 135 to 150 g were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high-fat diet and distilled water (po) or high-fat diet and sodium butyrate. Treatments lasted for 6 weeks. Results: Results showed that high-fat diet caused glucose dysmetabolism, elevated plasma triglyceride (TG), total cholesterol (TC), corticosterone, malondialdehyde (MDA), plasma and cardiac UA, and lactate dehydrogenase (LDH). High-fat diet also led to depressed reduced glutathione (GSH). Histological analysis of cardiac tissue showed cellular infarction, infiltration, and fibrosis in high-fat diet-fed rats. However, all these effects were ameliorated by BUT treatment. Conclusions: The findings here showed that high-fat diet resulted in glucose dysmetabolism and cardiac tissue damage through a uric acid (UA) - dependent mechanism and that butyrate (BUT) can protect against high-fat diet-induced cardiometabolic disorders through UA suppression and augmentation of glutathione antioxidant defenses. This study therefore demonstrates that UA is involved in high fat diet-induced cardiometabolic syndrome. However, data here shows that the UA - associated events in high fat diet will chronically engender cardiac tissue damage. Interestingly, with UA suppression, BUT treatment showed plausible beneficial glucoregulatory, anti-inflammatory and antioxidant properties which were potent enough to confer protection on the cardiac tissue preventing overt damage in high fat diet-fed rats. Therefore, BUT may be considered for the development of suitable therapeutic candidate in the treatment of metabolic syndrome and cardiac derangements associated with heightened UA.

Female Songbirds Can Initiate the Transition from a Migratory to a Reproductive Physiology during Spring Migration.

AbstractThe high energetic costs of both migration and reproduction and the physiological changes to support these costs suggest that these life-history stages should be compartmentalized with little overlap between stages. In contrast, previous studies have shown that male birds can initiate reproductive development during migration before arrival on the breeding grounds with increases in plasma testosterone levels and testis size. However, sex differences in seasonal gonadal function are now recognized as profound, and few studies to date have shown that females can initiate the costly, but critical, estrogen-dependent final stages of gonadal maturation and changes in liver function (yolk precursor synthesis, vitellogenesis) while on migration. Here, we show that female yellow warblers (Setophaga petechia) arrive on the breeding grounds with elevated plasma triglyceride levels compared with males. Some females had plasma triglyceride levels of 5-7 mmol L-1, suggesting that they arrived in a relatively advanced stage of yolk precursor production. Furthermore, we show that females that arrived with higher plasma triglyceride levels took less time to initiate their first clutch. Adaptive plasticity in the timing of the transition from a migratory to a reproductive physiology might help migrant birds buffer against a mismatch between timing of arrival and conditions on the breeding grounds and allow them to advance timing of breeding to maximize breeding productivity.

Atherosclerosis Development and Aortic Contractility in Hypercholesterolemic Rabbits Supplemented with Two Different Flaxseed Varieties.

Alpha-linolenic acid (ALA) is widely regarded as the main beneficial component of flax for the prevention of cardiovascular disease. We evaluated the effect of the transgenic flaxseed W86—which is rich in ALA—on the lipid profile, atherosclerosis progression, and vascular reactivity in hypercholesterolemic rabbits compared to the parental cultivar Linola with a very low ALA content. Rabbits were fed a basal diet (control) or a basal diet supplemented with 1% cholesterol, 1% cholesterol and 10% flaxseed W86, or 1% cholesterol and 10% Linola flaxseed. A high-cholesterol diet resulted in an elevated plasma cholesterol and triglyceride levels compared to the control animals. Aortic sections from rabbits fed Linola had lower deposits of foamy cells than those from rabbits fed W86. A potassium-induced and phenylephrine-induced contractile response was enhanced by a high-cholesterol diet and not influenced by the W86 or Linola flaxseed. Pretreatment of the aortic rings with nitro-L-arginine methyl ester resulted in a concentration-dependent tendency to increase the reaction amplitude in the control and high-cholesterol diet groups but not the flaxseed groups. Linola flaxseed with a low ALA content more effectively reduced the atherosclerosis progression compared with the W86 flaxseed with a high concentration of stable ALA. Aorta contractility studies suggested that flaxseed ameliorated an increased contractility in hypercholesterolemia but had little or no impact on NO synthesis in the vascular wall.