Decreased Plasma Lipid Research Articles

Liver-specific mitochondrial amidoxime-reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models.

Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear. Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques. In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet. Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.

Abstract 3041: APOB Gene Deletion Increases The Expression Of Vitamin D Binding Protein In Human Hepatoma Cells

High plasma apolipoprotein B (apoB)-containing lipoproteins are both a biomarker and a causal mediator of many metabolic diseases. Inhibition of APOB mRNA decreases plasma lipid levels but at a risk of lipid accumulation in tissues. To understand the global consequences of reduced apoB synthesis, we generated a human hepatoma (Huh-7) cell culture model system deficient in apoB. ApoB deficient Huh-7 cells (Ako) were generated using the CRISPR/Cas9 system. Total RNA for transcriptomics and overnight conditioned media for proteomics and lipidomics was obtained from the Ako and Huh-7 cells (n=3). Statistical analysis was done using Student’s t-test while comparing two groups, p < 0.05 was considered significant. APOB gene deletion significantly reduced APOB mRNA and protein levels in the Ako cells compared to control cells. Ako cells supported apoB48 secretion when transfected with apoB48 expression plasmids. These cells did not accumulate significant amounts of triglyceride. KEGG pathway analysis of RNA-Seq data showed a significant increase in DNA replication/repair pathway and complement/coagulation cascade in the Ako cells. The most downregulated pathways included the PI3k-Akt signaling and MAPK signaling pathways. Differential gene expression analysis identified vitamin D binding protein (VDB, gene GC ) mRNA as the most highly upregulated transcript in Ako cells. The Ako media secretome contained significantly higher amounts of VDB compared to control Huh-7. Furthermore, targeted lipidomics of the secretome showed significant increases in media ergocalciferol. Our qPCR and western blot analysis confirmed increased expression of VDB mRNA and protein secretion in the Ako cells as compared to the Huh-7 cells. We established a cell culture model deficient in secreting apoB-containing lipoproteins. These cells, however, support the assembly and secretion of apoB48 when transfected with apoB48 expression plasmid. A major consequence of apoB deficiency was upregulation of the VDB expression. We interpret these data to suggest that human hepatoma cells have two differentially regulated pathways for the transport of vitamin D. In the absence of apoB-lipoprotein assembly, these cells upregulate VDB to augment secretion of vitamin D.

Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir.

In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.

Sweet Basil (Ocimum basilicum) Products as Medical Treatment of Human Diseases

Sweet basil is cultivated for production of essential oils, dry leaves as a culinary herb, condiment/spice or as an ornamental plant. It is used as an ingredient in Ocimum basilicum L. commonly called as Sweet Basil belongs to family Lamiaceace is native plant of Indo-Malayan region. It is called the “king of herbs” which contains plenty of phytochemicals with significant nutritional as well as antioxidant capabilities and health benefits. Sweet basil is cultivated for production of essential oils, dry leaves as a culinary herb, condiment/spice or as an ornamental plant. It is used as an ingredient in various dishes and food preparations, especially in the Mediterranean cuisine. The unique array of active constituents called flavonoids found in basil provides protection at cellular level. Orientin and vicenin are two water-soluble flavonoids that have been of particular interest in basil. Essential oil of basil, obtained from its leaves, has demonstrated the ability to inhibit several species of pathogenic bacteria that have become resistant to commonly used antibiotic drugs. Due to its antimicrobial, insecticidal activity and very pleasant aroma, basil essential oil is widely used in the food, pharmaceutical, cosmetic, and aromatherapy industries. In addition, now-a-days public prefers natural food additives hence naturally derived antimicrobial agents from basil have become more important in antimicrobial packaging as they present a perceived lower risk to consumers. Aromatic leaves and flowering parts of O. basilicum are traditionally used as stimulant and tonic agents used in folk remedies to treat various ailments such as poor digestion, stomach-ache, feverish illnesses, nausea, abdominal cramps, gastro-enteritis, migraine, insomnia, depression, gonorrhoea, dysentery, and chronic diarrhoea exhaustion. Externally, they have been applied for the treatment of acne, loss of smell, insect stings, snake bites, and skin infections. Rosmarinic acid (RA) is the most biologically active compound present in Basil. The extract of the herb is used in preventing cardiovascular diseases through improved diet and several antioxidant compounds it contains display a high antioxidant power. The extracts have been shown to display important effects at the cellular level, including a platelet antiaggregant property and inhibitory activity against HIV to decrease plasma lipid content. Some of the medicinal properties that basil has are that it can be used to cure coughs, headaches, abdominal aches, and kidney diseases. Basil oils have been classified into four chemotypes according to their chemical composition and geographical source. The European type, cultivated in Europe, USA, and Africa, is characterized by linalool and methyl chavicol as the major oil constituents. The Reunion type, located in the Comoros and Seychelles Islands, Africa, and Reunion Island, is characterized by a high concentration of methyl chavicol. Tropical type originated from India, Pakistan, Guatemala, Haiti, and Africa is rich in methyl cinnamate. Another basil chemotype, with eugenol as the main component, is common in North Africa, Russia, Eastern Europe, and parts of Asia. In addition to these, other basil oils have also been reported which contained various quantities of linalool, camphor, methyl chavicol, methyl cinnamate, and eugenol.

Prebiotic‐Based Nanoamorphous Atorvastatin Attenuates Nonalcoholic Fatty Liver Disease by Retrieving Gut and Liver Health

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial and composite, with the disorder of lipid metabolism‐induced lipotoxicity being one of the main risk factors. Atorvastatin (AT), the most widely prescribed lipid‐lowering drug, has pleiotropic actions benefiting NAFLD treatment. However, low absorption rate in the gut and potential disruption of AT on gut flora hindered its further applications. Notably, gut dysbiosis is involved in and is thus a promising management strategy for NAFLD. In this study, we constructed a prebiotic‐based AT nanoamorphous (PANA) to improve the efficacy of AT against NAFLD by retrieving liver and gut health. After oral administration, PANA showed superior drug accumulation in the liver tissue compared with pure AT. Moreover, PANA intervention effectively restored gut healthiness, indicated by reconstructed gut flora, and improved intestinal immunity, barrier integrity, and inflammation. Consequently, compared with AT, PANA treatment caused profound inhibition of weight gain and fat deposition, decreased plasma lipid levels, and alleviated hepatic steatosis and liver inflammation. The transcriptome analysis in the gut and liver tissues identified improved immunity and inflammation as potential mechanisms. This study suggests a promising strategy to treat NAFLD, assisted with nanotechnology in synergy with functional biomaterials.

Differential Effect of Dietary Supplementation with a Soybean Oil Enriched in Oleic Acid versus Linoleic Acid on Plasma Lipids and Atherosclerosis in LDLR-Deficient Mice.

Both monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) play important roles in lipid metabolism, and diets enriched with either of these two fatty acids are associated with decreased cardiovascular risk. Conventional soybean oil (CSO), a common food ingredient, predominantly contains linoleic acid (LA; C18:2), a n-6 PUFA. Recently, a modified soybean oil (MSO) enriched in oleic acid (C18:1), a n-9 MUFA, has been developed, because of its improved chemical stability to oxidation. However, the effect of the different dietary soybean oils on cardiovascular disease remains unknown. To test whether diets rich in CSO versus MSO would attenuate atherosclerosis development, LDL receptor knock-out (LDLR-KO) mice were fed a Western diet enriched in saturated fatty acids (control), or a Western diet supplemented with 5% (w/w) LA-rich CSO or high-oleic MSO for 12 weeks. Both soybean oils contained a similar amount of linolenic acid (C18:3 n-3). The CSO diet decreased plasma lipid levels and the cholesterol content of VLDL and LDL by approximately 18% (p < 0.05), likely from increased hepatic levels of PUFA, which favorably regulated genes involved in cholesterol metabolism. The MSO diet, but not the CSO diet, suppressed atherosclerotic plaque size compared to the Western control diet (Control Western diet: 6.5 ± 0.9%; CSO diet: 6.4 ± 0.7%; MSO diet: 4.0 ± 0.5%) (p < 0.05), independent of plasma lipid level changes. The MSO diet also decreased the ratio of n-6/n-3 PUFA in the liver (Control Western diet: 4.5 ± 0.2; CSO diet: 6.1 ± 0.2; MSO diet: 2.9 ± 0.2) (p < 0.05), which correlated with favorable hepatic gene expression changes in lipid metabolism and markers of systemic inflammation. In conclusion, supplementation of the Western diet with MSO, but not CSO, reduced atherosclerosis development in LDLR-KO mice independent of changes in plasma lipids.

1360-P: Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency

Backgrounds: It's well known that calorie restriction (CR) brings striking benefits in metabolic improvement with complex and unclear mechanism. In this study, we aimed to investigate the specific manifestation and possible mechanisms of metabolism in CR mice. Methods: B6 mice were randomly assigned to three groups: (1) chow diet (control) , (2) chow diet with 40% calorie restriction (CR) , (3) high-fat diet (HFD) . The metabolism status and related examination were performed after 12 weeks of feeding. Results: In this study, we found that CR increased fasting blood glucose and plasma insulin, as well as reduced insulin sensitivity reflected by insulin tolerance test. Comparing to the control mice, the decrease of phosphorylation levels of IRS-1 including serine307 and tyrosine632 residues, and AKT (threonine308) after insulin rejection further confirmed that CR induced insulin resistance. Different from insulin resistance induced by HFD, CR improved glucose tolerance and reduced gluconeogenesis. Meanwhile, CR led to absolute lipid reduction, manifested in decreased plasma lipid, liver lipid deposition and fat mass. In contrast, liver glycogen increased dramatically. Fasting glycogen was twice as much as that of HFD group and 20 times as that of control group. Furthermore, the CR increased p-PYGL, p-GSK3β and decreased p-GS notably indicating active glycogen synthesis and decomposition. Subsequently, we found that CR increased plasma corticosterone and decreased plasma c-reactive protein (CRP) compared with control and HFD groups, while plasma corticosterone and CRP in HFD were higher than those in control group. Additionally, CR lowered levels of orexigenic neuropeptides and elevated levels of anorexigenic neuropeptides. Conclusions: Our study suggested that CR induced lipid insufficiency and stress from starvation, resulting in physiological insulin resistance and enhanced glycogen metabolism, including increased glycogen synthesis, glycogenolysis and glycogen content. Disclosure L.Hu: None. X.Xia: None. Y.Gu: None. J.Yin: None. Funding National Natural Science Foundation of China (No. 82070885) ,Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20172025)

Novel efficacious microRNA-30c analogs reduce apolipoprotein B secretion in human hepatoma and primary hepatocyte cells

High plasma lipid levels have been demonstrated to increase cardiovascular disease risk. Despite advances in treatments to decrease plasma lipids, additional therapeutics are still needed because many people are intolerant or nonresponsive to these therapies. We previously showed that increasing cellular levels of microRNA-30c (miR-30c) using viral vectors or liposomes reduces plasma lipids and atherosclerosis. In this study, we aimed to synthesize potent miR-30c analogs that can be delivered to hepatoma cells without the aid of viral vectors and lipid emulsions. We hypothesized that modification of the passenger strand of miR-30c would increase the stability of miR-30c and augment its delivery to liver cells. Here, we report the successful synthesis of a series of miR-30c analogs by using different chemically modified nucleosides. In these analogs, we left the active sense strand untouched so that its biological activity remained unaltered, and we modified the passenger strand of miR-30c to enhance the stability and uptake of miR-30c by hepatoma cells through phosphorothiorate linkages and the addition of GalNAc. We show that these analogs significantly reduced apolipoprotein B secretion in Huh-7 human hepatoma cells and human primary hepatocytes without affecting apolipoprotein A1 secretion and cellular lipid levels. Our results provide a proof of concept that the passenger strand of miR-30c can be modified to increase its stability and delivery to cells while retaining the potency of the sense strand. We anticipate these miR-30c analogs will be useful in the development of more efficacious analogs for the treatment of hyperlipidemias and cardiovascular diseases.

Novel insights into the effect of Xiaoyao san on corticosterone-induced hepatic steatosis: inhibition of glucocorticoid receptor/perilipin-2 signaling pathway

Abstract Objective: Xiaoyao san (XYS) is a classic traditional Chinese medicinal formula. It has been clinically administered to regulate liver function. However, its mechanisms in glucocorticoid-induced hepatic steatosis are unknown. This study aimed to investigate whether XYS protects against corticosterone (CORT)-induced hepatic steatosis, and to explore its mechanism. Methods: High-fat diet mice induced with hepatic steatosis by 2 mg/kg CORT were administered 2.56 g/kg or 5.12 g/kg XYS daily for 7 weeks. The effects of XYS on hepatic steatosis in mice were evaluated by H&amp;E and Oil Red O staining and by measuring their plasma lipids (triglyceride, total cholesterol, and free fatty acids). The mechanism of XYS against hepatic steatosis was investigated by network pharmacology, immunohistochemistry, western blotting, and gain-of-function/loss-of-function experiments. Results: XYS alleviated CORT-induced steatosis, decreased plasma lipids, and inhibited glucocorticoid receptor (GR) activation in the liver. Network pharmacology data indicated that XYS may have mitigated hepatic steatosis via GR which mediated adipose differentiation-related protein (ADFP). Gain-of-function/loss-of-function experiments in vitro confirmed that GR positively regulated ADFP expression. Conclusions: XYS ameliorated CORT-induced hepatic steatosis by downregulating the GR/ADFP axis and inhibiting lipid metabolism. Our studies implicate that XYS is promising as a therapy for CORT-induced hepatic steatosis, and lay the foundation for designing novel prophylactic and therapeutic strategies on CORT-induced hepatic steatosis.

Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice

ObjectiveMultiple genome-wide association studies (GWAS) have identified SNPs in the 8q24 locus near TRIB1 that are significantly associated with plasma lipids and other markers of cardiometabolic health, and prior studies have revealed the roles of hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs are additionally associated with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health. MethodsWe investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) fed on chow and high-fat diet (HFD). Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue. ResultsTrib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice indicates that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in the lipoprotein lipase (LPL) activity that likely underlies the triglyceride phenotype. ConclusionsThis study shows that adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on the further mechanisms by which TRIB1 regulates plasma lipids and metabolic health.

Decreased plasma lipid levels in a statin-free Danish primary health care cohort between 2001 and 2018

BackgroundLipid levels in blood have decreased considerably during the past decades in the general population partly due to use of statins. This study aims to investigate the trends in lipid levels between 2001 and 2018 in a statin-free population from primary health care, overall and by sex and age.MethodsIn a cohort of 634,119 patients from general practice with no diagnoses or medical treatments that affected lipid levels of total cholesterol (TC; n = 1,574,339) between 2001 and 2018 were identified. Similarly, measurements of low-density lipoprotein cholesterol (LDL-C; n = 1,302,440), high-density lipoprotein cholesterol (HDL-C; n = 1,417,857) and triglycerides (TG; n = 1,329,477) were identified.ResultsMean TC decreased from 5.64 mmol/L (95% CI: 5.63–5.65) in 2001 to 5.17 mmol/L (95% CI: 5.16–5.17) in 2018 while LDL-C decreased from 3.67 mmol/L (95% CI: 3.66–3.68) to 3.04 mmol/L (95% CI: 3.03–3.04). Women aged 70–74 years experienced the largest decreases in TC levels corresponding to a decrease of 0.7 mmol/L. The decrease in LDL-C levels was most pronounced in men ≥85 years with a decrease of 0.9 mmol/L. For both genders, TC and LDL-C levels increased with advancing age until around age 50. After menopause the women had higher TC and LDL-C levels than the men. The median (geometric mean) TG level decreased by 0.4 mmol/L from 2001 to 2008, after which it increased slightly by 0.1 mmol/L until 2018. During life the TG levels of the men were markedly higher than the women’s until around age 65–70. HDL-C levels showed no trend during the study period.ConclusionsThe levels of TC and LDL-C decreased considerably in a statin-free population from primary health care from 2001 to 2018. These decreases were most pronounced in the elderly population and this trend is not decelerating. For TG, levels have started to increase, after an initial decrease.

Purple Corn Anthocyanin Affects Lipid Mechanism, Flavor Compound Profiles, and Related Gene Expression of Longissimus Thoracis et Lumborum Muscle in Goats.

Simple SummaryNatural flavor compounds can stimulate people’s senses of smell and taste; as indicators of food sensory quality, such compounds influence the acceptance by consumers. In addition, natural antioxidants are becoming popular among consumers because they are safe and have no adverse side effects. Purple corn anthocyanins are polyphenolic compounds with natural antioxidant properties that exist widely in nature. Research has shown that anthocyanins can provide extra electrons to the free radicals, preventing lipid oxidation and improving muscle volatile components. However, no information is available concerning the effect of feeding anthocyanin on goat meat volatile compounds. This was the first study to investigate the effects of dietary anthocyanins from purple corn supplementation on lipid mechanism, body composition, volatile compound profiles, and related gene expression in the longissimus thoracis et lumborum muscle of goats. The current study indicates that the consumption of purple corn anthocyanin by growing goats improves mutton flavor by decreasing plasma lipid metabolism parameters and by modulating the abundance of several flavor-related genes in the longissimus thoracis et lumborum muscle. The results will help to understand the mechanism of action of anthocyanins on the flavor compounds, providing the rationale for anthocyanins regulating mutton flavor through related signaling pathways of ruminants in future studies.The current study aimed to investigate the effect of anthocyanins on muscle flavor compound profiles in goats. Goats in three groups were fed a basic diet or a diet supplemented with 0.5 g/d or 1 g/d anthocyanin-rich purple corn pigment (PCP). Compared to the control group, plasma total cholesterol was significantly decreased (p < 0.05) in the anthocyanin groups. The feeding of anthocyanin increased (p < 0.05) flavor compound types and total alcohol level, whereas it decreased (p < 0.05) total hydrocarbons, aromatics, esters, and miscellaneous compounds in the longissimus thoracis et lumborum muscle (LTL). Adding PCP to the diet enriched (p < 0.05) vegetal, herbaceous, grease, and fruity flavors compared to the control group. The 0.5 g/d PCP group had increased (p < 0.05) abundance of peroxisome proliferator-activated receptor gamma, but there was a decreased (p < 0.05) level of lipoprotein lipase in LTL. Collectively, this study indicated that anthocyanin can improve mutton flavor by decreasing plasma lipid parameters and by modulating the abundance of several flavor-related genes of goats.

Rhamnan sulphate from green algae Monostroma nitidum improves constipation with gut microbiome alteration in double-blind placebo-controlled trial

Rhamnan sulphate (RS), a sulphated polysaccharide from Monostroma nitidum, possesses several biological properties that help in treating diseases such as viral infection, thrombosis, and obesity. In the present study, we first administered RS (0.25 mg/g food volume) orally to high-fat diet-treated mice for 4 weeks. RS increased the faecal volume and calorie excretion with decreased plasma lipids, which was in accordance with the results of our previous zebrafish study. Notably, as the excretion amount by RS increased in the mice, we hypothesised that RS could decrease the chance of constipation in mice and also in human subjects because RS is considered as a dietary fibre. We administrated RS (100 mg/day) to subjects with low defaecation frequencies (3–5 times/week) for 2 weeks in double-blind placebo-controlled manner. As a result, RS administration significantly increased the frequency of dejection without any side effects, although no effect was observed on the body weight and blood lipids. Moreover, we performed 16s rRNA-seq analysis of the gut microbiota in these subjects. Metagenomics profiling using PICRUSt revealed functional alternation of the KEGG pathways, which could be involved in the therapeutic effect of RS for constipation.

Akebia saponin D ameliorates metabolic syndrome (MetS) via remodeling gut microbiota and attenuating intestinal barrier injury

Metabolic syndrome (MetS) is a complex, multifactorial disease which lead to an increased risk of cardiovascular disease, type 2 diabetes, and stroke. However, selective, and potent drugs for the treatment of MetS are still lacking. Previous studies have found that Akebia saponin D (ASD) has beneficial effects on metabolic diseases such as obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). Therefore, our study was designed to determine the effect and mechanism of action of ASD against MetS in a high-fat diet (HFD) induced mouse model. ASD significantly decreased plasma lipid and insulin resistance in these mice, and a targeted approach using metabolomic analyses of plasma and feces indicated that glucose and lipids in these mice crossed the damaged intestinal barrier into circulation. Furthermore, ASD was able to increase lipid excretion and inhibit intestinal epithelial lipid absorption. Results for gut microbiota composition showed that ASD significantly reduced HFD-associated Alistipes, Prevotella, and enhanced the proportions of Butyricimonas, Ruminococcus, and Bifidobacterium. After 14 weeks of ASD/fecal microbiota transplantation (FMT) interventions the developed gut barrier dysfunction was restored. Additionally, RNA-seq revealed that ASD reduced the lipid-induced tight junction (TJ) damage in intestinal epithelial cells via down-regulation of the PPAR-γ-FABP4 pathway in vitro and that use of the PPAR-γ inhibitor (T0070907) was able to partially block the effects of ASD, indicating that the PPAR-γ/FABP4 pathway is a critical mediator involved in the improvement of MetS. Our results demonstrated that ASD not only modifies the gut microbiome but also ameliorates the HFD-induced gut barrier disruption via down-regulation of the PPAR-γ-FABP4 pathway. These findings suggest a promising, and novel therapeutic strategy for gut protection against MetS.

PL-S2, a homogeneous polysaccharide from Radix Puerariae lobatae, attenuates hyperlipidemia via farnesoid X receptor (FXR) pathway-modulated bile acid metabolism

Polysaccharides are important active constituents of Radix Puerariae lobatae (RPL). In this study, a novel homogeneous polysaccharide from RPL was successfully obtained by HP-20 macroporous resin and purified by Sepharose G-100 column chromatography. Nuclear magnetic resonance (NMR) analysis showed that the main glycosidic bonds were composed of α-1,3-linked and α-1,4-linked glucose. The molecular weight of PL-S2 was 18.73 kDa. The hypolipidemic effect of PL-S2 on hyperlipidemic rats was evaluated in histopathology and metabolomics analyses. PL-S2 significantly reduced plasma lipid levels and inhibited bile acid metabolism. We also demonstrated that treatment with PL-S2 activated FXR, CYP7A1, BESP, and MRP2 in rat liver. Our findings first indicate that PL-S2 decreases plasma lipid levels in hyperlipidemic rats by activating the FXR signaling pathway and promoting bile acid excretion. Therefore, PL-S2 derived from RPL is implicated as a functional food factor with lipid-regulating activity, and highlighted as a potential food supplement for the treatment of hyperlipidemia.

Beneficial effects on growth, haematic indicators, immune status, antioxidant function and gut health in Juvenile Nile tilapia (Oreochromis niloticus) by dietary administration of a multi‐strain probiotic

The present study was conducted to administer a commercial multi‐strain probiotic (MP), Yilibao (Bacillus velezensis:Bacillus cereus:Lactobacillus casei = 2:2:1), in Nile tilapia, Oreochromis niloticus. In terms of aerobic Bacillus spp. counts, we produced five diets containing 0, 0.34, 1.68, 3.36 and 6.72 g/kg of MP dry product (Control, T1, T2, T3, T4). Seven hundred and fifty tilapia juveniles (13.26 ± 0.01 g) distributed into 25 tanks in five replications were fed their diet for eight weeks. Results showed that fish fed T3 and T4 diets displayed significantly higher final body weight and weight gain (p < .05). Further, all MP‐treated fish exhibited remarkably decreased plasma lipid profiles (cholesterol, triglycerides) (p < .05) and fish fed T3 and T4 diets displayed significantly higher plasma myeloperoxidase activity and complement C3 content (p < .05). Additionally, fish fed T3 and T4 diets exhibited significantly promoted total antioxidant capacity, glutathione peroxidase activity, glutathione level and declined malondialdehyde content in the plasma and/or liver (p < .05). Moreover, significantly elevated chymotrypsin activity, villus height and intraepithelial lymphocytes counts were found in fish fed T3 and T4 diets (p < .05). As fish fed T3 and T4 diets surpassed the other treatments in growth, immune–antioxidative status and gut health, the recommended dose for tilapia is 3.36–6.72 g/kg.

3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice.

AimsAtherosclerosis is a chronic inflammatory disease involving immunological and metabolic processes. Metabolism of tryptophan (Trp) via the kynurenine pathway has shown immunomodulatory properties and the ability to modulate atherosclerosis. We identified 3-hydroxyanthranilic acid (3-HAA) as a key metabolite of Trp modulating vascular inflammation and lipid metabolism. The molecular mechanisms driven by 3-HAA in atherosclerosis have not been completely elucidated. In this study, we investigated whether two major signalling pathways, activation of SREBPs and inflammasome, are associated with the 3-HAA-dependent regulation of lipoprotein synthesis and inflammation in the atherogenesis process. Moreover, we examined whether inhibition of endogenous 3-HAA degradation affects hyperlipidaemia and plaque formation.Methods and results In vitro, we showed that 3-HAA reduces SREBP-2 expression and nuclear translocation and apolipoprotein B secretion in HepG2 cell cultures, and inhibits inflammasome activation and IL-1β production by macrophages. Using Ldlr−/− mice, we showed that inhibition of 3-HAA 3,4-dioxygenase (HAAO), which increases the endogenous levels of 3-HAA, decreases plasma lipids and atherosclerosis. Notably, HAAO inhibition led to decreased hepatic SREBP-2 mRNA levels and lipid accumulation, and improved liver pathology scores.ConclusionsWe show that the activity of SREBP-2 and the inflammasome can be regulated by 3-HAA metabolism. Moreover, our study highlights that targeting HAAO is a promising strategy to prevent and treat hypercholesterolaemia and atherosclerosis.

Chlorinated persistent organic pollutants and type 2 diabetes - a population-based study with pre- and post- diagnostic plasma samples

PDS 63: Chemicals and metals: health effects, Exhibition Hall (PDS), Ground floor, August 27, 2019, 10:30 AM - 12:00 PM Background: Persistent organic pollutants (POPs) have been associated with type 2 diabetes (T2D), but causality is uncertain. Objective: Within longitudinal population-based data from northern Sweden, we assessed how POPs associated with T2D prospectively and cross-sectionally, and further investigated factors related to individual changes in POP concentrations. Methods: For 129 case-controls pairs matched by age, sex and date of sampling, plasma concentrations of HCB, p,p´-DDE, dioxin-like PCBs (PCB-118, -156), and non-dioxin like PCBs (PCB-74, -99, -138 -153, -170, -180, -183 -187) were analyzed twice (baseline and follow-up, 9-20 years apart). The cases received their T2D diagnose between baseline and follow-up. Prospective (using baseline data) and cross-sectional (using follow-up data) odds ratios (ORs) for T2D on lipid standardized POPs (HCB, p,p´-DDE, ∑DL-PCBs, ∑NDL-PCBs) were estimated using conditional logistic regression, adjusting for body mass index (BMI) and plasma lipids. The influence of BMI, weight-change, and plasma lipids on longitudinal changes in POP concentrations were evaluated among non-diabetic individuals (n=306). Results: POPs were associated with T2D in both the prospective and cross-sectional assessments. Of a standard deviation increase in POPs, prospective ORs ranged 1.42 (95% CI: 0.99, 2.06) for ∑NDL-PCBs to 1.55 (95% CI: 1.01, 2.38) for HCB (p<0.05 only for HCB), and cross-sectional ORs ranged 1.62 (95% CI: 1.13; 2.32) for p,p´-DDE to 2.06 (95% CI: 1.29, 3.28) for ∑DL-PCBs (p<0.05 for all POPs). In analyses of non-diabetic individuals, higher baseline BMI, decreased weight and decreased plasma lipid concentrations were associated with a slower decrease of POPs. Cases had, besides a higher BMI, reduced cholesterol and weight gain at follow-up compared to controls, which can explain the higher ORs in the cross-sectional assessments. Discussion: The indication that individuals’ body fat history might influence POP-T2D associations through decreased elimination rate, weakens the epidemiological support for a causal association.

Tanshinone IIA ameliorates non-alcoholic fatty liver disease through targeting peroxisome proliferator-activated receptor gamma and toll-like receptor 4.

ObjectiveTo investigate the cellular mechanisms of action of tanshinone IIA on the fatty liver disease induced by a high-fat diet in an animal model of non-alcoholic fatty liver disease (NAFLD).MethodsAdult male Sprague Dawley rats were randomized into one of three groups: regular rat diet (CON group) for 4 months; high-fat diet (HFD group) for 4 months; HFD for 2 months followed by tanshinone IIA treatment plus HFD (TAN group) for a further 2 months. A range of physical and biochemical markers of lipid accumulation and fatty liver disease were measured and compared between the groups.ResultsTanshinone IIA treatment significantly reduced fat accumulation in the liver and plasma lipid levels that had been increased by HFD. The toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway was silenced by tanshinone IIA treatment. Tumour necrosis factor-α and interleukin-6 were reduced by tanshinone IIA. Hepatocyte apoptosis was inhibited by tanshinone IIA. Tanshinone IIA upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ), which resulted in an improvement in the oxidative status.ConclusionTanshinone IIA ameliorates NAFLD by targeting PPAR-γ and TLR4, resulting in decreased plasma lipids and oxidative stress, suggesting this strategy may form the basis of novel NAFLD therapies.

The Structurally Engineered Fatty Acid Icosabutate Improves Lipid Metabolism And Reduces Severity Of Atherogenesis In Mice

Background and Aims: Icosabutate is a structurally engineered fatty acid derived from eicosapentaenoic acid (EPA) which decreases plasma triglycerides (TG) and non-HDL lipoprotein cholesterol (VLDL-C and LDL-C) in hyperlipidemic patients. We examined the mechanism by which icosabutate decreases plasma lipids and affects atherosclerotic lesion formation.