Hepatic Cholesterol Metabolism Research Articles

Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol.

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation

Background & aimsDysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. Approach & resultsThe expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. ConclusionsInhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. Impact and implicationsPCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.

Genetic Deletion of Hepatic NCOR1 regulates the bile acid metabolism and leads to reduction in atherosclerosis

Abstract Background The nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Since NCOR1 transrepresses the function of several nuclear receptors involved in hepatic lipid transport and synthesis, we hypothesized that genetic NCOR1 deletion in the liver alters lipid metabolism and atherosclerosis development. Methods To test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoraco-abdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional level. Results This study findings demonstrated that specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, hepatic cholesterol and triglyceride contents were decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion. Conclusions Our data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion. Hepatocyte NCOR1 may therefore provide a novel target for development of anti-atherosclerotic drugs.

Deletion of hepatic small heterodimer partner ameliorates development of nonalcoholic steatohepatitis in mice

Small heterodimer partner (SHP, Nr0b2) is an orphan nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Shp−/− mice are resistant to diet-induced obesity and hepatic steatosis. In this study, we explored the potential role of SHP in the development of nonalcoholic steatohepatitis (NASH). A 6-month Western diet (WD) regimen was used to induce NASH. Shp deletion protected mice from NASH progression by inhibiting inflammatory and fibrotic genes, oxidative stress, and macrophage infiltration. WD feeding disrupted the ultrastructure of hepatic mitochondria in WT mice but not in Shp−/− mice. In ApoE−/− mice, Shp deletion also effectively ameliorated hepatic inflammation after a 1 week WD regimen without an apparent antisteatotic effect. Moreover, Shp−/− mice resisted fibrogenesis induced by a methionine- and choline-deficient diet. Notably, the observed protection against NASH was recapitulated in liver-specific Shp−/− mice fed either the WD or methionine- and choline-deficient diet. Hepatic cholesterol was consistently reduced in the studied mouse models with Shp deletion. Our data suggest that Shp deficiency ameliorates NASH development likely by modulating hepatic cholesterol metabolism and inflammation.

Organoid Establishment of Long-Term Culture Using Primary Mouse Hepatocytes and Evaluation of Liver Function.

Primary hepatocytes and various animal models have traditionally been used in liver function tests to assess the effects of nutrients. However, these approaches present several limitations such as time consumption, high cost, the need for facilities, and ethical issues in primary mouse hepatocytes and animal models. In this study, we constructed liver organoids from primary mouse hepatocytes (OrgPH) to replace primary hepatocytes and animal models. We isolated primary mouse hepatocytes from 6- to 10-week-old male C57BL/6J mice using the two-step collagenase method, and generated liver organoids by clustering the cells in Matrigel. To assess the hepatic function of OrgPH, we examined specific liver markers and gene expressions related to hepatic glucose, ethanol, and cholesterol metabolism. Over a 28-day culture period, liver-specific markers, including Alb, Arg1, G6pc, and Cyp1a1, increased or remained stable in the OrgPH. However, they eventually decreased in primary hepatocytes. Glucose and ethanol metabolism-related gene expression levels exhibited a similar tendency in AML12 cells and OrgPH. However, the expression levels of cholesterol metabolism-related genes displayed an opposite trend in OrgPH compared with those in AML12 cells. These results agree with those of previous studies involving in vivo models. In conclusion, our study indicates that OrgPH can retain liver function and mimic the hepatocytic physiology of mouse in vivo models. Therefore, organoids originating from primary mouse hepatocytes are potentially useful as an animal-free method for evaluating the safety and toxicity of health functional foods and a replacement for animal models.

Maternal high-calorie diet feeding programs hepatic cholesterol metabolism and Abca1 promoter methylation in the early life of offspring

Maternal high-calorie diet feeding can dramatically increase the susceptibility of metabolic diseases in offspring. However, whether maternal high-calorie diet feeding can program hepatic cholesterol metabolism in the early life of offspring is less understood, and the epigenetic mechanisms underlying this intergenerational effect, especially during the early life of offspring, are unknown. Female C57BL/6J mice were randomly assigned to a high-calorie diet or control diet before and during gestation, and lactation. Lipid metabolism was evaluated in male offspring at weaning. Gene expressions and quantitative methylation levels of key genes associated with hepatic cholesterol metabolism were further evaluated in offspring at weaning age. We found that maternal high-calorie diet feeding resulted in higher body weight, hypercholesterolemia, elevated total cholesterol in liver homogenates, and fat deposits in the liver in offspring at weaning. For key genes that regulate cholesterol metabolism in liver, we showed lower Hmgcr and Ldlr, and higher Abca1 mRNA and protein expressions in offspring from dams fed with high-calorie diet at weaning age. We further found that maternal high-calorie diet feeding significantly decreased Abca1 methylation level in offspring, with lower methylation levels of both CpG 11 and CpG 22 sites. Interestingly, we found that Abca1 methylation level was negatively associated with hepatic Abca1 mRNA expression in offspring from dams fed with high-calorie diet and controls. However, the expressions of key genes associated with hepatic cholesterol metabolism were not significant between fetuses of dams fed with high-calorie diet and control diet. In conclusion, our results indicate that maternal high-calorie diet feeding results in aberrant lipid metabolism, including hypercholesterolemia and fat deposits in the liver of offspring as early as weaning age. Furthermore, maternal high-calorie feeding can program hepatic cholesterol metabolism and Abca1 methylation in the early life of offspring.

Hepatic steatosis is associated with dysregulated cholesterol metabolism and altered protein acetylation dynamics in chickens

BackgroundHepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.MethodsNinety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.ResultsThe rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins (DEPs) interacted with differentially acetylated proteins (DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group (P < 0.05). Lipidomics detected a variety of sphingolipids (SPs) and glycerophospholipids (GPs) were negatively correlated with hepatic steatosis (r ≤ −0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.ConclusionsIn addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.

Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion

BackgroundThe nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Recently, we demonstrated that the deletion of macrophage NCOR1 aggravates atherosclerosis by promoting CD36-triggered foam cell formation via PPARG derepression.PurposeSince NCOR1 modulates the function of several key regulators involved in hepatic lipid and bile acid metabolism, we hypothesized that its deletion in hepatocytes alters lipid metabolism and atherogenesis.MethodsTo test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoracoabdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional levels.ResultsOur data demonstrate that liver-specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet, plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, the hepatic cholesterol content was decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion.ConclusionsOur data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion.

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis

Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

Gut Microbiota and Acylcarnitine Metabolites Connect the Beneficial Association between Estrogen and Lipid Metabolism Disorders in Ovariectomized Mice.

Decreased estrogen level is one of the main causes of lipid metabolism disorders and coronary heart disease in women after menopause. Exogenous estradiol benzoate is effective to some extent in alleviating lipid metabolism disorders caused by estrogen deficiency. However, the role of gut microbes in the regulation process is not yet appreciated. The objective of this study was to investigate the effects of estradiol benzoate supplementation on lipid metabolism, gut microbiota, and metabolites in ovariectomized (OVX) mice and to reveal the importance of gut microbes and metabolites in the regulation of lipid metabolism disorders. This study found that high doses of estradiol benzoate supplementation effectively attenuated fat accumulation in OVX mice. There was a significant increase in the expression of genes enriched in hepatic cholesterol metabolism and a concomitant decrease in the expression of genes enriched in unsaturated fatty acid metabolism pathways. Further screening of the gut for characteristic metabolites associated with improved lipid metabolism revealed that estradiol benzoate supplementation influenced major subsets of acylcarnitine metabolites. Ovariectomy significantly increased the abundance of characteristic microbes that are significantly negatively associated with acylcarnitine synthesis, such as Lactobacillus and Eubacterium ruminantium group bacteria, while estradiol benzoate supplementation significantly increased the abundance of characteristic microbes that are significantly positively associated with acylcarnitine synthesis, such as Ileibacterium and Bifidobacterium spp. The use of pseudosterile mice with gut microbial deficiency greatly facilitated the synthesis of acylcarnitine due to estradiol benzoate supplementation and also alleviated lipid metabolism disorders to a greater extent in OVX mice. IMPORTANCE Our findings establish a role for gut microbes in the progression of estrogen deficiency-induced lipid metabolism disorders and reveal key target bacteria that may have the potential to regulate acylcarnitine synthesis. These findings suggest a possible route for the use of microbes or acylcarnitine to regulate disorders of lipid metabolism induced by estrogen deficiency.

Effect of Copper Exposure on the Cholesterol Metabolism in Broiler Liver.

Copper (Cu) is a kind of widely used dietary supplement in poultry production, and a common environmental pollutant at the same time. Excess Cu exposure has been reported to accumulate in the liver and induce cytotoxicity, but the effect of Cu toxicity on hepatic cholesterol metabolism is still uncertain. Herein, we aimed to reveal the effect of excess Cu on the liver and primary hepatocytes of broilers at various concentrations. We found that 110mg/kg Cu supplement remarkably increased blood cholesterol levels by detecting serum TC, LDL-C, and HDL-C in the broilers, while there was no significant difference in 220 and 330mg/kg Cu supplements. In addition, high Cu exposure resulted in severe hepatic steatosis and hepatic cord derangement in the broilers. Oil red O staining of primary hepatocytes showed that Cu treatment caused intracellular neutral lipid accumulation. However, the hepatic TC content indicated a downward trend in both liver tissues and hepatocytes after Cu exposure. Furthermore, the expression of cholesterol metabolism-related indicators (SREBP2, HMGCR, LDLR, and CYP7A1) was notably decreased in the Cu-treated groups. While the expression of the key enzyme of cholesterol esterification (ACAT2) did not change significantly. Taken together, our findings preliminarily revealed excess Cu-induced hepatic cholesterol metabolism dysfunction, providing a deeper understanding of the molecular mechanisms of Cu-induced hepatotoxicity.

Pleurotus Ostreatus Polyphenols Extract Based Diets Enhanced Hepatic Cholesterol Metabolism Related Gene Expression in Weaned Rabbits

Mycelium of oyster mushroom (Pleurotus ostreatus) contain active flavonoids that have antioxidant and suppressive cholesterolemic effects. This study was conducted to explore the mechanism and effects of dietary Pleurotus ostreatus phenolic supplementation on levels of cellular cholesterol deposition and metabolism in weaned rabbits. Twenty four (24) weaned rabbits were randomly divided into three groups with eight (8) replicates per group in a complete randomized design experiment. Rabbits were fed control diet (basal) and/or a control diet supplemented with 450 mg/kg or 900 mg/kg P. ostreatus phenolic extracts (POPE) for seven weeks. Blood and liver samples were collected to determine serum adiponectin and hepatic cholesterolic related genes. 3-hydroxyl-3 methyl-glutaryl coenzyme A reductase (HMG-CoAR) and cholesterol 7 α-hydroxylase (CTP7A1) mRNA levels and sterol regulatory element binding transcription factor 1(SREBF1) were down regulated while, Low-density lipoprotein receptor (LDL-R) and sterol co enzyme A desaturase gene (SCD) were up regulated to decrease fat mass, serum triglycerides (TG), serum total cholesterol and low density lipoprotein cholesterol (LDL-C) levels in rabbits on 450 and 900mg/kg P. ostreatus phenolic extract supplementation diets. Serum adiponectin concentration and High density lipoprotein cholesterol (HDL-C) increased from 22.5 to 32.09 and 1.21 to 1.56 mmol/L, respectively for control and POPE based diets. The results suggested that dietary supplementation of P. ostreatus extract at 900 mg/ kg diets could improve lipid metabolism in rabbits by regulating hepatic cholesterol metabolism gene expression and optimizing fatty acid uptake and synthesis.

Lavender Essential Oil Modulates Hepatic Cholesterol Metabolism in HepG2 Cells.

Cholesterol is an essential lipid that guarantees several biological processes in eukaryotic cells. Its metabolism is regulated by a complex protein network that could be significantly influenced by numerous exogenous sources, such as essential oils (EOs). For instance, it has been speculated that monoterpenoid and sesquiterpenoid compounds contained in lavender essential oil (LEO) may exert important hypocholesterolemic activities. However, the molecular mechanisms by which LEO influences cholesterol homeostasis are not characterized. In this work, we evaluated the ability of LEO to regulate the protein network that controls cholesterol metabolism in the HepG2 cell line. The main findings indicate that LEO administration increases intracellular cholesterol content. Concurrently, LEO affects the expression of proteins involved in cholesterol uptake, biosynthesis, and trafficking. These effects are partially mediated by terpinene-4-ol, one of the most abundant compounds in LEO. These results demonstrate that LEO modulates cholesterol metabolism in hepatic cells.

Brazilian green propolis extracts modulate cholesterol homeostasis in a preclinical guinea pig model: an in vitro and in vivo study.

Green propolis produced by Apis melífera bees, having Baccharis dracunculifolia D.C. (Asteraceae) as the primary botanical source, has been used in traditional medicine to treat numerous disorders. However, studies evaluating propolis' potential in treating cardiovascular diseases via its effects on cholesterol metabolism are lacking. Therefore, this study investigated the effects of green propolis extracts on lipid metabolism in hypercholesterolemic guinea pigs. Chemical characterization of ethanolic extracts of green propolis samples was undertaken using HPLC. The in vitro characterization included an evaluation of the antioxidant capacity of the hydroalcoholic extract of green propolis (DPPH and FRAP assays) and its ability to act as an inhibitor of the HMG-CoA reductase enzyme. In vivo, we investigated the effect of the hydroalcoholic extract of green propolis on lipid metabolism in hypercholesterolemic guinea pigs. Results obtained validated previous reports of significant antioxidant activity. HPLC analysis confirmed that coumaric acid, artepillin C, and baccharin were the most common and abundant compounds in green propolis samples among the studied compounds. Furthermore, the compounds in these extracts acted as effective HMG-CoA reductase inhibitors in vitro. In vivo assays demonstrated that a hypercholesterolemic diet significantly reduced serum levels of the HDL cholesterol fraction. Simvastatin and propolis hydroalcoholic extracts promoted a significant increase in HDL cholesterol, suggesting that these extracts can improve the serum lipid profile of hypercholesterolemic guinea pigs. Results obtained in this study provide a perspective on the possible hypocholesterolemic effect of green propolis, suggesting that it can improve the serum lipid profile in hypercholesterolemic guinea pigs.

Effects of thiacloprid exposure on microbiota-gut-liver axis: Multiomics mechanistic analysis in Japanese quails.

Neonicotinoid insecticides (NNIs) are the most widely used class of pesticides globally. However, NNIs may cause adverse health effects, including chronic liver disease, and perturbation of the gut microbiota. Thiacloprid (THI) is one of the NNIs widely used in agriculture. Therefore, it is essential to elucidate effects of THI on the microbiota-gut-liver axis to assess the risk of chronic liver disease following exposure to NNIs. This study aimed at investigating whether THI exposure promoted liver injury by altering the gut microbiota and related metabolites. In this study, healthy male quails were exposed to 2 or 4mg/kg THI or 0.75 % (w/v) saline once daily for 6 weeks, respectively. Metabolomics, 16S rRNA sequencing, and transcriptomic methods were performed to analyze the toxic mechanisms of THI in Japanese quails. We found that THI evoked damage and disruption to intestinal barrier function, leading to increased harmful substances such as lipopolysaccharide (LPS) and phenylacetic acid entering the liver. Besides, our results showed significantly altered hepatic bile acid and cholesterol metabolism in THI-exposed quails, with abnormal liver lipid metabolism, showing severe liver injury, fibrosis, and steatosis compared with the control quails. In conclusion, THI exposure aggravates liver injury via microbiota-gut-liver axis.

Effects of Bilberry Extract on Hepatic Cholesterol Metabolism in HepG2 Cells

Bilberry (Vaccinium myrtillus L.), rich in polyphenols, has been claimed to have lipid-lowering effects, but its underlying mechanisms remain unclear. The effects of bilberry extract (BE) with antioxidant properties on hepatic lipid metabolism were investigated by measuring the genes for cholesterol biosynthesis and flux in HepG2 cells. The mRNA and protein levels of genes involved in cholesterol biosynthesis such as sterol regulatory element-binding protein 2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase were decreased in BE-treated cells. BE posttranscriptionally upregulated low-density lipoprotein receptor in HepG2 cells. There was a marked reduction in genes for very low-density lipoprotein assembly by BE treatment. Furthermore, the expression of canalicular transporter for cholesterol and bile acids, such as ABCG8 and ABCB11, was significantly elevated by BE treatment. Downregulation of lipogenic genes and upregulation of fatty acid oxidation-related genes were observed in BE-treated HepG2 cells. The expressions of sirtuins were altered by BE treatment. These results support that the effects of BE on hepatic cholesterol metabolism may be attributed to the regulation of genes for hepatic cholesterol biosynthesis, transport and efflux.

Saikosaponins ameliorate hyperlipidemia in rats by enhancing hepatic lipid and cholesterol metabolism

Ethnopharmacological relevanceHyperlipidemia is the systemic manifestation of abnormal lipid metabolism, characterized by elevated circulating levels of cholesterol and triglyceride and a high risk of cardiovascular events. Radix Bupleuri (RB) is a traditional Chinese herbal product used to treat liver diseases. Our previous study demonstrated that Saikosaponins (SSs), the most potent bioactive ingredients in RB, ameliorate hepatic steatosis. However, whether SSs have anti-hyperlipidemia effects and plausible underlying mechanisms remain elusive. Aim of the studyTo comprehensively evaluate the lipid-lowering potential of SSs against hyperlipidemia in rats. Materials and methodsRNA sequencing and untargeted metabolomics approaches were applied to analyze the changes in the liver transcriptome and serum lipid profile in long-term high-fat diet feeding-induced hyperlipidemia rats in response to SSs or positive drug simvastatin (SIM) intervention. ResultsOur data revealed that SSs significantly alleviated HFD-induced hypertriglyceridemia and hypercholesterolemia. Combined with the analysis of gene ontology enrichment analysis and gene set enrichment analysis, we found that SSs remarkably repaired the unbalanced blood lipid metabolic spectrum in a dose-dependent manner by increasing the hepatic uptake of circulating fatty acids and facilitating mitochondrial respiration in fatty acid oxidation, comparable to SIM group. In addition, SSs markedly modulated cholesterol clearance by promoting intracellular cholesterol efflux, HDL remodeling, LDL particle clearance, and bile acid synthesis. SSs also efficiently protected the liver from lipid overload-related oxidative stress and lipid peroxidation, as well as substantially exaggerated inflammatory response. ConclusionOur research not only unraveled the intricate mechanisms underlying the lipid-lowering functions of SSs but also provided novel perspectives on developing an SSs-based therapeutic strategy for the treatment of hyperlipidemia. ClassificationMetabolism.

Selected Soybean Varieties Regulate Hepatic LDL-Cholesterol Homeostasis Depending on Their Glycinin:β-Conglycinin Ratio.

Clinical studies indicate that the consumption of soybean protein might reduce cholesterol and LDL levels preventing the development of atherosclerotic cardiovascular diseases. However, soybean variety can influence soybean protein profile and therefore affect soybean protein health-promoting properties. This study investigated the composition and effects of nineteen soybean varieties digested under simulated gastrointestinal conditions on hepatic cholesterol metabolism and LDL oxidation in vitro. Soybean varieties exhibited a differential protein hydrolysis during gastrointestinal digestion. Soybean varieties could be classified according to their composition (high/low glycinin:β-conglycinin ratio) and capacity to inhibit HMGCR (IC50 from 59 to 229 µg protein mL-1). According to multivariate analyses, five soybean varieties were selected. These soybean varieties produced different peptide profiles and differently reduced cholesterol concentration (43-55%) by inhibiting HMGCR in fatty-acid-stimulated HepG2 hepatocytes. Selected digested soybean varieties inhibited cholesterol esterification, triglyceride production, VLDL secretion, and LDL recycling by reducing ANGPTL3 and PCSK9 and synchronously increasing LDLR expression. In addition, selected soybean varieties hindered LDL oxidation, reducing the formation of lipid peroxidation early (conjugated dienes) and end products (malondialdehyde and 4-hydroxynonenal). The changes in HMGCR expression, cholesterol esterification, triglyceride accumulation, ANGPTL3 release, and malondialdehyde formation during LDL oxidation were significantly (p &lt; 0.05) correlated with the glycinin:β-conglycinin ratio. Soybean varieties with lower glycinin:β-conglycinin exhibited a better potential in regulating cholesterol and LDL homeostasis in vitro. Consumption of soybean flour with a greater proportion of β-conglycinin may, consequently, improve the potential of the food ingredient to maintain healthy liver cholesterol homeostasis and cardiovascular function.

A multi-marker integrative analysis reveals benefits and risks of bariatric surgery

Bariatric surgery (BS) is an effective intervention for severe obesity and associated comorbidities. Although several studies have addressed the clinical and metabolic effects of BS, an integrative analysis of the complex body response to surgery is still lacking. We conducted a longitudinal data study with 36 patients with severe obesity who were tested before, 6 and 12 months after restrictive BS for more than one hundred blood biomarkers, including clinical, oxidative stress and metabolic markers, peptide mediators and red blood cell membrane lipids. By using a synthetic data-driven modeling based on principal component and correlation analyses, we provided evidence that, besides the early, well-known glucose metabolism- and weight loss-associated beneficial effects of BS, a tardive, weight-independent increase of the hepatic cholesterol metabolism occurs that is associated with potentially detrimental inflammatory and metabolic effects. Canonical correlation analysis indicated that oxidative stress is the most predictive feature of the BS-induced changes of both glucose and lipids metabolism. Our results show the power of multi-level correlation analysis to uncover the network of biological pathways affected by BS. This approach highlighted potential health risks of restrictive BS that are disregarded with the current practice to use weight loss as surrogate of BS success.