Reduced Plasma Triglyceride Research Articles

Short hydrocarbon stapled ApoC2-mimetic peptides activate lipoprotein lipase and lower plasma triglycerides in mice.

Defects in lipolysis can lead to hypertriglyceridemia, which can trigger acute pancreatitis and is also associated with cardiovascular disease. Decreasing plasma triglycerides (TGs) by activating lipoprotein lipase (LPL) with ApoC2 mimetic peptides is a new treatment strategy for hypertriglyceridemia. We recently described a dual ApoC2 mimetic/ApoC3 antagonist peptide called D6PV that effectively lowered TG in several mouse models but has limitations in terms of drug development. The aim of this study was to create the next generation of ApoC2 mimetic peptides. We employed hydrocarbon staples, as well as select amino acid substitutions, to make short single helical mimetic peptides based on the last helix of ApoC2. Peptides were first tested for their ability to activate LPL and then in hypertriglyceridemia mouse models. All-atom simulations of peptides were performed in a lipid-trilayer model of TG-rich lipoproteins to discern their possible mechanism of action. We designed a single stapled peptide called SP1 (21 residues), and a double stapled (stitched) peptide called SP2 (21 residues) and its N-terminal acylated analogue, SP2a. The hydrocarbon staples increased the amphipathicity of the peptides and their ability to bind lipids without interfering with LPL activation. Indeed, from all-atom simulations, the conformations of SP1 and SP2a are restrained by the staples and maintains the proper orientation of the LPL activation motif, while still allowing their deeper insertion into the lipid-trilayer model. Intraperitoneal injection of stapled peptides (1-5 umoles/kg) into ApoC2-hypomorphic mice or human ApoC3-transgenic resulted in an 80%-90% reduction in plasma TG within 3 h, similar to the much longer D6PV peptide (41 residues). Other modifications (replacement L-Glu20, L-Glu21 with their D-isomers, N-methylation of Gly19, Met2NorLeu and Ala1alpha-methylAla substitutions, N-terminal octanoylation) were introduced into the SP2a peptide. These changes made SP2a highly resistant to proteolysis against trypsin, pepsin, and Proteinase K, while maintaining similar efficacy in lowering plasma TG in mice. We describe a new generation of ApoC2 mimetic peptides based on hydron carbon stapling that are at least equally potent to earlier peptides but are much shorter and resistant to proteolysis and could be further developed into a new therapy for hypertriglyceridemia.

1595-P: Empagliflozin Improves Nephropathy and Heart Failure with Preserved Ejection Fraction Despite Limited Effects on NASH in a Novel Obese Diabetic Hamster Model

Introduction: Sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) has shown significant benefits for patients with diabetic nephropathy and heart failure with preserved ejection fraction (HFpEF), but the effects on nonalcoholic steatohepatitis (NASH) and liver fibrosis remain unclear. To further investigate the benefits of EMPA on these comorbidities, we established a novel diet-induced obese diabetic hamster model with human-like NASH and lipoprotein cholesterol metabolism, that also develops nephropathy and HFpEF. Methods: Obesity, NASH, and HFpEF were induced with a 20-week free choice diet, which presents hamsters with a choice between control chow or high fat/cholesterol diet, and normal water or 10% fructose water. After 20 weeks of diet, obese hamsters were intraperitoneally injected with streptozotocin (STZ) to induce diabetes and were then treated orally once daily for 5 weeks with vehicle or EMPA 30mg/kg. Results: Compared with vehicle, EMPA reduced hyperglycemia (vehicle: 373 +/- 43 mg/dL; EMPA: 182 +/- 30 mg/dL, p<0.01), increased pancreatic insulin content (+146%, p<0.05), significantly reduced plasma triglycerides and moderately raised LDL-cholesterol levels, as expected. However, EMPA did not improve NASH (including hepatocyte ballooning score) and liver fibrosis. EMPA reduced glomerular filtration rate and proteinuria (p=0.06 for both vs. vehicle), and significantly reduced urine albumin-to-creatinine ratio (-35%, p<0.01). In addition, EMPA showed significant improvement in HFpEF with reduced E/A and E’/E ratios with no alteration in ejection fraction, as measured by echocardiography. Conclusion: EMPA improves kidney parameters and HFpEF despite limited effects on NASH in obese diabetic hamsters. This preclinical model with multiple comorbidities will be useful to evaluate the combination of EMPA or other antidiabetic therapies with drugs targeting NASH. Disclosure F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. C. Dubroca: Employee; CARDIOMEDEX. T. Sulpice: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. Employee; CARDIOMEDEX. Stock/Shareholder; CARDIOMEDEX.

The Effects of Prolonged Treatment with Cemtirestat on Bone Parameters Reflecting Bone Quality in Non-Diabetic and Streptozotocin-Induced Diabetic Rats.

Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Experimental animals were assigned to four groups: non-diabetic rats, non-diabetic rats treated with cemtirestat, diabetic rats, and diabetic rats treated with cemtirestat. Higher levels of plasma glucose, triglycerides, cholesterol, glycated hemoglobin, magnesium, reduced femoral weight and length, bone mineral density and content, parameters characterizing trabecular bone mass and microarchitecture, cortical microarchitecture and geometry, and bone mechanical properties were determined in STZ-induced diabetic versus non-diabetic rats. Treatment with cemtirestat did not affect all aforementioned parameters in non-diabetic animals, suggesting that this drug is safe. In diabetic rats, cemtirestat supplementation reduced plasma triglyceride levels, increased the Haversian canal area and slightly, but insignificantly, improved bone mineral content. Nevertheless, the insufficient effect of cemtirestat treatment on diabetic bone disease does not support its use in the therapy of this complication of type 1 diabetes mellitus.

Effect of Rhodiola rosea Rhizome and Punica granatum Fruit Peel on the Metabolic Processes and Physiological Activity of Rats Fed with Excessively Fat Diet.

Rhodiola rosea (golden root) and Punica granatum (pomegranate), as well as a number of other species of medicinal plants, exert an array of biological effects: adaptogenic, antioxidant and anti-inflammatory. However, there are not enough contemporary studies of their influence on metabolic processes, especially in cases of imbalanced diet. Lipid dysregulation is the main reason for many diseases, including obesity, cardiovascular disorders, non-alcoholic fatty liver disease, hypertension, atherosclerosis and insulin resistance. Recently, a growing amount of evidence has suggested the positive effects of certain natural nutrients on lipid metabolism. The work aims to define the general effect of golden root rhizome and pomegranate peel on physiological activity and metabolic processes in model animals fed with excessively fat diet. This study is relevant for the development of drugs and food additives for treatment and prophylaxis of metabolism disorders. In a 30-day experiment, we determined the effect of golden root (Rhodiola rosea L.) rhizome and pomegranate (Punica granatum L.) peel on the physiological activity and metabolic processes of 24 laboratory rats consuming a high-fat diet. The physical activity was evaluated according to the mass gain of animals and change in the relative mass of the internal organs, and also the functional conditions of the central nervous system, as demonstrated by the indicators of the locomotor activity and emotional status, determined in the open field test. The influence on the metabolic processes was revealed by biochemical and clinical blood analyses. Body mass of rats fed with golden root (R. rosea) reached 125.8 % of the initial body mass; when fed on pomegranate (P. granatum), it reached 123.9 %; and the control group reached only 111.5 % of the initial body mass. The rhizomes of R. rosea in the diet of male rats during the month of the experiment did not cause significant changes in the relative organ mass, and the pomegranate peel fruits led to a decrease in the thymus relative mass, as well as liver and brain. R. rosea rhizomes in the rats' diet led to an increase in the activity of alkaline phosphatase, and also to a decrease in the concentration of urea and urea nitrogen. Diet supplemented with R. rosea also contributed to a strong decrease in plasma concentrations of bilirubin and triglycerides (up to 57.0 % compared with the concentration in the control group). The rhizomes of R. rosea contributed to an unreliable decrease in the atherogenicity index. The pomegranate peel also greatly increased alkaline phosphatase activity and reduced plasma triglyceride concentrations. In addition, in rats consuming the peel of P. granatum, blood glucose concentration decreased. Under the influence of P. granatum, a strong increase in the atherogenic index of plasma (up to 518.6 % of the control) was observed because of a decrease in the concentration of high-density lipoproteins (up to 57.1 %) and a simultaneous elevation of the concentration of low-density lipoproteins (up to 158.3 % of the control). Open field test between groups remained without significant changes. The results indicate that the rhizome of R. rosea and peel of P. granatum are safe as food additives to high-fat diet and did not cause pathological changes and side effects, and at the same time significantly influence the metabolic processes (lipid and carbohydrate). Our study theoretically substantiates the use of R. rosea rhizome and P. granatum peel for the production of nutraceutical and pharmacological products for the correction of metabolic disorders of people and animals. Doses and periods of their application require further research.

A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis

Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established.Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis.Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity.HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity.

The implications of maternal overnutrition on offspring metabolic and neuroimmune development are well-known. Increasing evidence now suggests that maternal obesity and poor dietary habits during pregnancy and lactation can increase the risk of central and peripheral metabolic dysregulation in the offspring, but the mechanisms are not sufficiently established. Furthermore, despite many studies addressing preventive measures targeted at the mother, very few propose practical approaches to treat the damages when they are already installed. Here we investigated the potential of cannabidiol (CBD) treatment to attenuate the effects of maternal obesity induced by a cafeteria diet on hypothalamic inflammation and the peripheral metabolic profile of the offspring in Wistar rats. We have observed that maternal obesity induced a range of metabolic imbalances in the offspring in a sex-dependant manner, with higher deposition of visceral white adipose tissue, increased plasma fasting glucose and lipopolysaccharides (LPS) levels in both sexes, but the increase in serum cholesterol and triglycerides only occurred in females, while the increase in plasma insulin and the homeostatic model assessment index (HOMA-IR) was only observed in male offspring. We also found an overexpression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα), interleukin (IL) 6, and interleukin (IL) 1β in the hypothalamus, a trademark of neuroinflammation. Interestingly, the expression of GFAP, a marker for astrogliosis, was reduced in the offspring of obese mothers, indicating an adaptive mechanism to in utero neuroinflammation. Treatment with 50 mg/kg CBD oil by oral gavage was able to reduce white adipose tissue and revert insulin resistance in males, reduce plasma triglycerides in females, and attenuate plasma LPS levels and overexpression of TNFα and IL6 in the hypothalamus of both sexes. Together, these results indicate an intricate interplay between peripheral and central counterparts in both the pathogenicity of maternal obesity and the therapeutic effects of CBD. In this context, the impairment of internal hypothalamic circuitry caused by neuroinflammation runs in tandem with the disruptions of important metabolic processes, which can be attenuated by CBD treatment in both ends.

Potential of Caffeic Acid and 10-Dehydrogingerdione as Lipid Regulators Relevant to Their Inhibitory Effect on miR-122 and ATP Citrate Lyase Activity in Diabetic Hyperlipidemic Rats

The present study aimed to illustrate the hypolipemic effect of 10-Dehydrogengardione (10-DHG) or caffeic acid (CA) with reference to the role of microRNA-122 (miR-122) and ATP citrate lyase (ACLY) activity. Diabetic hyperlipidemia was induced in rats, and then randomly classified into three groups. The first one received only a CCT-diet for 6 weeks and was referred to as the positive control. The other two groups received 10-DHG (10 mg/kg/day) or CA (50 mg/kg/day), orally for 6 weeks along with a CCT-diet. Another group of normal rats was included, received a normal diet, and was referred to as the negative control. Either 10-DHG or CA significantly decreased MiR-122 expression and appeared more remarkable in the CA group by 15.5%. The 10-DHG greatly enhanced phosphorylated form of AMP activated protein kinase (p-AMPK) activity, more than CA by 1.18-fold, while the latter exerted more inhibitory effect on ACLY, and fatty acid synthase (FAS) activities compared with 10-DHG (p < 0.05). Both drugs significantly decreased hydroxy methyl glutaryl coenzyme A (HMG-COA) reductase activity, which appeared more remarkable in 10-DHG, and significantly decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) along with a high density lipoprotein cholesterol (HDL-C) increase. The 10-DHG ameliorated the hepatic tissue lesions greatly, more than CA. The 10-DHG or CA significantly inhibited MiR-122, hepatic FAS, and ACLY levels along with p-AMPK activation. This subsequently led to reduced plasma TG, cholesterol levels, and blood glucose improvement and, indeed, may explain their mechanisms as hypolipemic agents.

Increased BAT Thermogenesis in Male Mouse Apolipoprotein A4 Transgenic Mice.

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.

Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia.

Atherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD. We combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks. Co-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight. The adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.

Role of Goldenberry (Fruits with Husk) Extract in Ameliorating the Architecture and Osmotic Fragility of Red Blood Cells in Obese Rats.

Goldenberry (GB) is a promising fruit that can be a constituent in many possible nourishments. No notifications were obtained regarding the impact of exposure to goldenberry extract in the viewpoint of blood rheological properties as well as erythrocyte osmotic fragility of red blood cells (RBCs) in obese rats. A substantial reduction in plasma triglyceride, total cholesterol, and LDL, with a considerable increment in HDL levels relative to the obese group (p ≤ 0.05), was observed in rats receiving low and high doses of GB, accompanied by restoration of SOD activity and GSH levels. Rheological parameters of rats' blood have been studied over a wide range of shear rates (225-1875 s-1). A significant decrease in blood viscosity in rats who received low and high doses of GB extract was compatible with every shear rate compared to the control group. The shear stress values of the obese rats reduced appreciably (p ≤ 0.05) in all values of shear rate (from 75 to 500 s-1) proportional to the control group, while in the groups that received low and high doses of GB extract, shear stress was restored to the control values. Finally, administration of GB extract significantly decreased yield stress and indices of whole blood aggregation, with an extremely substantial increment in flow rate, in rats given low or high doses of GB compared to obese ones. The result also showed a decrease in both the average raised osmotic fragility and the hemolysis rate in rats after supplementation with low and high doses of GB extract.

Uncovering the physiological impacts of soybean meal replacement by Narbonne vetch (Vicia narbonensis) meal in rainbow trout (Oncorhynchus mykiss) diets: Towards the future and sustainable European aquaculture.

The identification and implementation of raw materials to replace fish meal (FM) or its major alternative, soybean meal (SBM), among other factors, is crucial for the sustainable growth of aquaculture. Narbonne vetch (Vicia narbonensis) meal (NVM) has previously been identified as a promising alternative raw material locally produced in Europe to replace SBM. Previous work has showed that 33% replacement of SBM by NVM treated with a commercially available phytase (Rovabio® PHY) does not compromise fish growth performance in a 63-day trial. Here, a deeper characterization of the potential use of NVM to replace SBM was performed to unveil any potential undesired physiological impact in rainbow trout (Oncorhynchus mykiss) juveniles with an initial weight of 38.04 ± 0.07 g. After a 63-day feeding trial, high (66%) SBM replacement by NVM (even when treated with Rovabio® PHY) had a negative impact on rainbow trout: decreasing the activity of alkaline proteases, trypsin, chymotrypsin, and α-amylase; inducing cell shrinkage in hepatocytes; and reducing plasma triglycerides and hepatic vitamin E (VE) levels. No biochemical alterations were observed in blood plasma glucose, cholesterol or redox enzymes, regardless of the % of SBM replacement and/or Rovabio® PHY treatment. In fish fed diets with 33% replacement of SBM by NVM (regardless of being treated with Rovabio® PHY or not), only a reduced content of plasma triglycerides, and a slight modification in the position of the nucleus in enterocytes (more intermediate) from the proximal intestine, were reported. Altered metabolism of both carbohydrates and VE was also confirmed at transcriptional level, possibly being related to the presence of non-starch polysaccharides (NSPs) in NVM. The present study identifies future strategies to improve the use of NVM as an alternative raw material to replace SBM, allowing greater sustainability, and a lower carbon footprint in European aquafeeds to be achieved.

Resistance to mild cold stress is greater in both wild-type and long-lived GHR-KO female mice.

Adapting to stress, including cold environmental temperature (eT), is crucial for the survival of mammals, especially small rodents. Long-lived mutant mice have enhanced stress resistance against oxidative and non-oxidative challenges. However, much less is known about the response of those long-lived mice to cold stress. Growth hormone receptor knockout (GHR-KO) mice are long-lived with reduced growth hormone signaling. We wanted to test whether GHR-KO mice have enhanced resistance to cold stress. To examine the response of GHR-KO mice to cold eT, GHR-KO mice were housed at mild cold eT (16°C) immediately following weaning. Longevity results showed that female GHR-KO and wild-type (WT) mice retained similar lifespan, while both male GHR-KO and WT mice had shortened lifespan compared to the mice housed at 23°C eT. Female GHR-KO and WT mice housed at 16°C had upregulated fibroblast growth factor 21 (FGF21), enhanced energy metabolism, reduced plasma triglycerides, and increased mRNA expression of some xenobiotic enzymes compared to females housed at 23°C and male GHR-KO and WT mice housed under the same condition. In contrast, male GHR-KO and WT mice housed at 16°C showed deleterious effects in parameters which might be associated with their shortened longevity compared to male GHR-KO and WT mice housed at 23°C. Together, this study suggests that in response to mild cold stress, sex plays a pivotal role in the regulation of longevity, and female GHR-KO and WT mice are more resistant to this challenge than the males.

Bergamot (Citrus bergamia) leaf extract improves metabolic, antioxidant and anti-inflammatory activity in skeletal muscles in a metabolic syndrome experimental model

Metabolic Syndrome (MetS), inflammation and oxidative stress contribute to impairment of skeletal muscle function. Bergamot (Citrus bergamia) leaf extract (BLE) has shown protective effects against comorbidities associated with MetS through its anti-inflammatory and antioxidant effects. The aim of this work was to elucidate the antioxidant and anti-inflammatory activity of BLE in skeletal muscles in an experimental model of MetS. Once metabolic syndrome was diagnosed, animals were divided into groups receiving different treatments for 10 weeks, including control diet (n = 10), control + BLE (n = 10), High Sugar-fat diet (HSF) (n = 10), HSF + BLE (n = 10). Evaluation included nutritional, metabolic and hormonal analyses, along with measurements of inflammatory status and oxidative stress in soleus and extensor digitorum longus (EDL) muscles. BLE showed positive metabolic effects, with a reduction of plasma triglycerides and insulin resistance and an increase in high-density lipoprotein cholesterol, and protective activity against oxidative stress and inflammation in Soleus and EDL muscles in animals with MetS.

Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by invivo and invitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15weeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.

Sichuan dark tea improves lipid metabolism and prevents aortic lipid deposition in diet-induced atherosclerosis model rats.

Sichuan dark tea (ST), Zangcha, is a traditional fermented Chinese tea found in Sichuan and Tibet and claimed for beneficial effects against lifestyle-related metabolic disorders. We examined the effects of ST on lipid metabolism and atherosclerosis. Sichuan dark tea was given to fat-rich diet-induced atherosclerosis model rats in comparison with dark-fermented Chinese Pu-erh tea (PT) and Japanese green tea (GT). After 8 weeks of feeding, ST and PT induced an increase in high-density lipoprotein (HDL)-cholesterol and a decrease in glucose, and ST decreased triglyceride in plasma. ST also induced low pH in the cecum. There was no significant change in their body weight among the fat-feeding groups but a decrease was found in the visceral fat and liver weight in the ST group. Accordingly, ST reduced lipid deposition in the aorta in comparison with PT and GT. ST increased mRNA of LXRα, PPARα, PPARγ, and ABCA1 in the rat liver. The extract of ST stimulated the AMPK pathway to increase the expression of ABCA1 in J774 cells and increased expression of lipoprotein lipase and hormone-sensitive lipase in 3T3L1 cells, consistent with its anti-atherogenic effects in rats. High-performance liquid chromatography analysis showed unique spectra of original specific compounds of caffeine and catechins in each tea extract, but none of them was likely responsible for these effects. Sichuan dark tea increases plasma HDL and reduces plasma triglyceride to decrease atherosclerosis through AMPK activation. Further study is required to identify specific components for the effects of this tea preparation.

Abstract 15473: A New Metabolic Phenotype in a Mouse Model of Chronic Kidney Disease and Atherosclerosis

Introduction: Patients with chronic kidney disease (CKD) experience significant cardiovascular morbidity and mortality. Vascular calcification is a hallmark of CKD and a strong predictor of atherosclerotic cardiovascular disease. Hypothesis: We hypothesize that CKD-induced vascular calcification potentiates atherosclerosis. Methods: First, wished to conduct a pilot study to confirm that a co-treatment of the low-density protein receptor mutant mice (Ldlr whc ) with a 0.2% adenine in a western diet will produce accelerated atherosclerosis, consistent with a well-known phenotype in the 5/6 nephrectomy model on an ApoE or Ldlr knockout background. Then we developed a two-step non-surgical mouse model in which the induction of calcification by a 0.2% adenine treatment was followed by western diet-induced hyperlipidemia. Results: Contrary to expected, the adenine and western diet (W+A) co-treatment resulted in a striking reduction of plasma triglycerides (TG), aortic root atherosclerosis, and liver lipids despite a fully penetrant CKD phenotype with tubulointerstitial damage, increased blood urea nitrogen, hyperphosphatemia, polyuria, vascular calcification, and osteoporosis. The two-step induction of CKD and atherosclerosis demonstrated partially normalized but reduced plasma triglycerides and liver lipid content, polyurea, and polydipsia in CKD mice, and there was no difference in atherosclerotic burden or plaque calcification between the groups. Interestingly we observed an increase in food and calorie intake and 24-hour glucose excretion in the urine in the pre-treated group compared with mice on a western diet without pre-treatment, while plasma glucose levels were not different between the groups. Conclusion: The paradoxical lack of dyslipidemia in mice treated with adenine provides an insight into the potential effects of tubulointerstitial kidney disease and nephrogenic diabetes incipits on lipid metabolism and atherosclerosis. 1

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

ObjectivePerfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We examined whether exposure to low-dose PFOA and GenX induces metabolic disturbances in mice, including NAFLD, dyslipidemia, and glucose tolerance, and studied the involvement of PPARα. MethodsMale C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg body weight/day PFOA, or 0.3 mg/kg body weight/day GenX while being fed a high-fat diet for 20 weeks. Glucose and insulin tolerance tests were performed after 18 and 19 weeks. Plasma metabolite levels were measured next to a detailed assessment of the liver phenotype, including lipid content and RNA sequencing. ResultsExposure to high-dose PFOA decreased body weight and increased liver weight in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides was dependent on PPARα. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. RNA sequencing showed that the effects of GenX on hepatic gene expression were entirely dependent on PPARα, while the effects of PFOA were mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR and CAR became more prominent. ConclusionOverall, we show that long-term and low-dose exposure to PFOA and GenX disrupts hepatic lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, the effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.

Tart Cherry Juice Reduces Plasma Triglycerides and CVD Risk Factor, But Does not Affect Indirect Measures of Insulin Resistance, in Overweight and Obese Subjects: A Randomized, Crossover Pilot Study

Tart Cherry Juice Reduces Plasma Triglycerides and CVD Risk Factor, But Does not Affect Indirect Measures of Insulin Resistance, in Overweight and Obese Subjects: A Randomized, Crossover Pilot Study

Efficacy and Safety of Empagliflozin in Type 2 Diabetes Mellitus Saudi Patients as Add-On to Antidiabetic Therapy: A Prospective, Open-Label, Observational Study.

The Saudi Food and Drug Authority (SFDA) approved sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2018. The efficacy and safety of empagliflozin (EMPA) have been confirmed in the U.S., Europe, and Japan for patients with type 2 diabetes mellitus (T2DM); however, analogous evidence is lacking for Saudi T2DM patients. Therefore, the current study aimed to assess the efficacy and safety of EMPA in Saudi patients (n = 256) with T2DM. This is a 12-week prospective, open-label, observational study. Adult Saudi patients with T2DM who had not been treated with EMPA before enrolment were eligible. The exclusion criteria included T2DM patients less than 18 years of age, adults with type one diabetes, pregnant women, paediatric population. The results related to efficacy included a significant decrease in haemoglobin A1c (HbA1c) (adjusted mean difference −0.93% [95% confidence interval (CI) −0.32, −1.54]), significant improvements in fasting plasma glucose (FPG) (−2.28 mmol/L [95% CI −2.81, −1.75]), and a reduction in body weight (−0.874 kg [95% CI −4.36, −6.10]) following the administration of 25 mg of EMPA once daily as an add-on to ongoing antidiabetic therapy after 12 weeks. The primary safety endpoints were the change in the mean blood pressure (BP) values, which indicated significantly reduced systolic and diastolic BP (−3.85 mmHg [95% CI −6.81, −0.88] and −0.06 mmHg [95% CI −0.81, −0.88], respectively) and pulse rate (−1.18 [95% CI −0.79, −3.15]). In addition, kidney function was improved, with a significant reduction in the urine albumin/creatinine ratio (UACR) (−1.76 mg/g [95% CI −1.07, −34.25]) and a significant increase in the estimated glomerular filtration rate (eGFR) (3.54 mL/min/1.73 m2 [95% CI 2.78, 9.87]). Furthermore, EMPA reduced aminotransferases (ALT) in a pattern (reduction in ALT > AST). The adjusted mean difference in the change in ALT was −2.36 U/L [95% CI −1.031, −3.69], while it was −1.26 U/L [95% CI −0.3811, −2.357] for AST and −1.98 U/L [95% CI −0.44, −3.49] for GGT. Moreover, in the EMPA group, serum high-density lipoprotein (HDL) significantly increased (0.29 mmol/L [95% CI 0.74, 0.15]), whereas a nonsignificant increase was seen in low-density lipoprotein (LDL) (0.01 mmol/L [95% CI 0.19, 0.18]) along with a significant reduction in plasma triglyceride (TG) levels (−0.43 mmol/L [95% CI −0.31, −1.17]). Empagliflozin once daily is an efficacious and tolerable strategy for treating Saudi patients with insufficiently controlled T2DM as an add-on to ongoing antidiabetic therapy.

Angiopoietin-like 3 (ANGPTL3) resides on HDL and LDL with the latter form having the highest lipase inhibitory activity

Background and Aims : Angiopoietin-like 3 (ANGPTL3) is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL). The impact of ANGPTL3 lowering has been shown to depend on the type of dyslipidemia: reduced LDL cholesterol in patients with familial hypercholesterolemia and reductions in plasma triglycerides in patients with chylomicronemia. This differential effect may be related to a difference in the association of ANGPTL3 with lipoproteins. We therefore hypothesized that ANGPTL3 resides on lipoproteins and that this affects its ability to suppress lipase activity.