Hepatic TG Levels Research Articles

Theabrownin inhibits obesity and non-alcoholic fatty liver disease in mice via serotonin-related signaling pathways and gut-liver axis

IntroductionNon-alcoholic fatty liver disease (NAFLD) with obesity seriously threats public health. Our previous studies showed that dark tea had more potential on regulating lipid metabolism than other teas, and theabrownin (TB) was considered to be a main contributor to the bioactivity of dark tea. ObjectivesThis in vivo study aims to reveal the effects and molecular mechanisms of TB on NAFLD and obesity, and the role of the gut-liver axis is explored. MethodsThe histopathological examinations, biochemical tests, and nuclear magnetic resonance were applied to evaluate the effects of TB on NAFLD and obesity. The untargeted metabolomics was used to find the key molecule for further exploration of molecular mechanisms. The 16S rRNA gene sequencing was used to assess the changes in gut microbiota. The antibiotic cocktail and fecal microbiota transplant were used to clarify the role of gut microbiota. ResultsTB markedly reduced body weight gain (67.01%), body fat rate (62.81%), and hepatic TG level (51.35%) in the preventive experiment. Especially, TB decreased body weight (32.16%), body fat rate (42.56%), and hepatic TG level (42.86%) in the therapeutic experiment. The mechanisms of action could be the improvement of fatty acid oxidation, lipolysis, and oxidative stress via the regulation of serotonin-related signaling pathways. Also, TB increased the abundance of serotonin-related gut microbiota, such as Akkermansia, Bacteroides and Parabacteroides. Antibiotics-induced gut bacterial dysbiosis disrupted the regulation of TB on serotonin-related signaling pathways in liver, whereas the beneficial regulation of TB on target proteins was regained with the restoration of gut microbiota. ConclusionWe find that TB has markedly preventive and therapeutic effects on NAFLD and obesity by regulating serotonin level and related signaling pathways through gut microbiota. Furthermore, gut microbiota and TB co-contribute to alleviating NAFLD and obesity. TB could be a promising medicine for NAFLD and obesity.

Mutant IDH1 attenuates hepatic lipogenesis through PTEN dependent pathway

Mutations in IDH1 (isocitrate dehydrogenases) such as R132H/Q/C, are frequently found in intrahepatic cholangiocarcinoma (IHCC). Mutant IDH1 proteins obtain an abnormal activity converting α-ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG), inhibiting the activity of multiple αKG-dependent dioxygenases, leading to metabolism disorder. Here, we depict a molecular network leading by mutant IDH1, that regulates hepatic lipid embolism using mouse model (KI) with IDH1 R132Q specifically knocked in liver. KI mice appear small and have notably reduced hepatic TG and FFA levels. Technically, mutant IDH1-mediated 2-HG can stabilize PTEN mRNA level probably depending on miR-32, activate Akt-SEBP1c signaling, leading to lipogenesis defect. Our study identifies a new role of oncometabolite 2-HG in inhibiting hepatic lipid metabolism.

Dysregulated autophagic activity induced in response to chronic intermittent hypoxia contributes to the pathogenesis of NAFLD.

Chronic intermittent hypoxia (CIH) is a pathological characteristic of obstructive sleep apnea (OSA) that has been linked to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The specific link between CIH, autophagic activity, and NAFLD, however, has not previously been characterized. The goal of this study was to assess the relationship between CIH-induced autophagy and the pathogenesis of OSA-associated NAFLD. Western blotting was used to assess the expression of proteins associated with lipid synthesis, endoplasmic reticulum (ER) stress, and autophagic activity. To establish an in vivo model system, C57BL/6 mice were subjected to CIH conditions for 8 h per day over a 12-week period, and were administered chloroquine (CQ) for 1 week prior to euthanization. Levels of serum and liver triglycerides in these animals were assessed, as were proteins related to hepatic autophagy, ER stress, and lipogenesis. qPCR was additionally used to assess hepatic inflammation-related gene expression, while transmission electron microscopy was used to monitor lipid droplet (LD) accumulation and ER morphology. OSA patients and CIH model mice exhibited increases in the expression of proteins associated with hepatic autophagy, ER stress, and lipogenesis. CIH was also associated with more pronounced LD accumulation, hepatic inflammation, and hepatic steatosis in these mice. While serum and hepatic TG and TC levels and serum ALT/AST were increased in response to CIH treatment, the administration of CQ to these mice led to reductions in ER stress-related proteins (XBP1, IRE1α, EIF2α) and lipogenesis-related proteins (ACC, SCD1, FASn), in addition to significantly reducing hepatic inflammation, steatosis, and LD accumulation in these animals. These results suggest that persistent CIH can drive dysregulated hepatic autophagic activity, hepatic steatosis, and ER stress, highlighting potential targets for therapeutic intervention aimed at preventing or treating OSA-associated NAFLD.

Amomum villosum Lour. Fruit extract mitigates hyperlipidemia through SREBP-2/LDLR/HMGCR signaling in high-cholesterol diet-fed mice

Amomum villosum Lour. (Zingiberaceae) is an herbal medicine used in Asian countries for various ailments. In the current experiment, the effect of AV water extract (AVE) on cholesterol-lowering capabilities along with its essential bio-molecular mechanisms have been examined. The efficiency of AVE against high-cholesterol diet (HCD)-generated hyperlipidemia was investigated using C57BL/6 mice. Mice have been divided to six categories: control group (normal diet), high-cholesterol diet (HCD), and HCD treated with AVE at 100, 200, and 500 mg/kg, or simvastatin 40 mg/kg for four weeks. AVE treated animal groups (100, 200, 500 mg/kg) had markedly lessened body mass increase (p < 0.01) and also had reduced liver and epididymal fat weights (p < 0.05) related to HCD alone batch. Hepatic TG levels in AVE 100 mg/kg, 200 mg/kg, and 500 mg/kg treated groups were meaningfully reduced by 13.32%, 14.61%, and 21.78%, respectively; and serum TG decreased by 25.65%, 31.97%, and 32.22%, respectively, compared to the HCD alone group. Serum TC was reduced by 11.17%, 12.48%, and 26.85% with AVE at 100, 200, and 500 mg/kg, respectively; and serum LDL-C declined by 10.08%, 18.50%, and 30.90% (p < 0.05) with AVE at 100, 200, and 500 mg/kg, respectively. Levels of mRNA expression including LDL receptor (LDLR), sterol regulatory element-binding protein 2 (SREBP2), and HMG-CoA reductase (HMGCR) were noticeably amplified by AVE (500 mg/kg) treatment. Similarly, AVE treatment significantly increased Hmgcr protein expression levels in a dose related fashion. These outcomes show that AVE displays a hypolipidemic effect and might function as a novel hypolipidemic therapy, further; they suggest a mechanism of action for this effect.

Astragalus Polysaccharides and Saponins Alleviate Liver Injury and Regulate Gut Microbiota in Alcohol Liver Disease Mice.

Astragalus, a medical and edible plant in China, shows several bioactive properties. However, the role of astragalus in attenuating alcoholic liver disease (ALD) is less clear. The objective of this project is to investigate the improving effect of astragalus saponins (AS) and astragalus polysaccharides (AP), which are the two primary constituents in astragalus on hepatic injury induced by alcohol, and the potential mechanisms of action. Different doses of AS (50 and 100 mg/kg bw) and AP (300 and 600 mg/kg bw) were orally given to alcohol-treated mice for four weeks. The results demonstrated that both AP and AS could reverse the increase of the levels of TC, TG, FFA, and LDL-C in serum, and the decrease of serum HDL-C content, as well as the elevation of hepatic TC and TG levels induced by alcohol. The activities of AST, ALT, ALP, and γ-GT in ALD mice were raised after AP and AS supplementation. The antioxidant markers (SOD, CAT, GSH, and GSH-Px) were obviously augmented and the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and hepatic histological variations were alleviated by AP and AS, which was in line with the levels of oxidative stress-associated genes (Keap1, Nfe2l2, Nqo1, and Hmox1) and inflammation-associated genes (Tlr4, Myd88 and Nfkb1). In addition, AS exerted a more efficient effect than AP and the results presented dose proportionality. Moreover, AS and AP could modulate the intestinal microbiota disturbance induced by alcohol. Overall, AS and AP administration could ameliorate lipid accumulation in the serum and liver, as well as hepatic function, oxidative stress, inflammatory response, and gut flora disorders in mice as a result of alcohol.

Rotundic acid ameliorates non-alcoholic steatohepatitis via SREBP-1c/ SCD1 signaling pathway and modulating gut microbiota

Non-alcoholic steatohepatitis (NASH) is a devastating form of non-alcoholic fatty liver disease (NAFLD) with distinguished hallmarks of steatosis and inflammation. Rotundic acid (RA) is a natural pentacyclic triterpene compound extracted from the bank of Ilex rotunda Thunb with a wide range of biological activities. The aim of the study is to evaluate the pharmacological effect and action mechanism of RA on NASH in vitro and in vivo. RA has weak lipid lowering ability in rat primary hepatocytes, significantly decreases serum LDL level, hepatic TG and TC levels and lipid droplets, reduces NAS compared with the NASH group, and alleviates hepatic inflammation. RA also enhances the recovery of intestinal bacterial community and intestinal-derived short-chain fatty acid caused by high food diet (HFD). Further investigation shows that RA protects against HFD-induced NASH via downregulating the expression of SREBP-1c/SCD1 signaling pathway and improving gut microbiota. These findings imply that RA might be helpful for the alleviation of NASH.

L-citrulline inhibits body weight gain and hepatic fat accumulation by improving lipid metabolism in a rat nonalcoholic fatty liver disease model.

BackgroundBody weight gain is a social issue all over the world. When body weight increased, hepatic fat accumulation also increased and it causes fatty liver disease. Therefore, developing a new treatment method and elucidating its mechanism is necessary. L‐citrulline (L‐Cit) is a free amino acid found mainly in watermelon. No reports regarding its effects on the improvement of hepatic steatosis and fibrogenesis are currently available. The aim of this study was to clarify the effect and the mechanism of L‐Cit on inhibition of body weight gain and hepatic fat accumulation in high‐fat and high‐cholesterol fed SHRSP5/Dmcr rats.MethodsL‐Cit or water (controls) was administered to six‐week‐old male SHRSP5/Dmcr rats by gavage for nine weeks. We recorded the level of body weight and food intake while performing the administration and sacrificed rats. After that, the blood and lipid metabolism‐related organs and tissues were collected and analyzed.ResultsL‐Cit treatment reduced body weight gain and hepatic TC and TG levels, and serum levels of AST and ALT. L‐Cit enhanced AMPK, LKB1, PKA, and hormone‐sensitive lipase (HSL) protein phosphorylation levels in the epididymal fat. L‐Cit treatment improved steatosis as revealed by HE staining of liver tissues and enhanced AMPK and LKB1 phosphorylation levels. Moreover, activation of Sirt1 was higher, while the liver fatty acid synthase (FAS) level was lower. Azan staining of liver sections revealed a reduction in fibrogenesis following L‐Cit treatment. Further, the liver levels of TGF‐β, Smad2/3, and α‐SMA, fibrogenesis‐related proteins and genes, were lower in the L‐Cit‐treated group.ConclusionsFrom the results of analysis of the epididymal fat and the liver, L‐Cit inhibits body weight gain and hepatic fat accumulation by activating lipid metabolism and promoting fatty acid β‐oxidation in SHRSP5/Dmcr rats.

Enzyme-Treated Zizania latifolia Extract Protects against Alcohol-Induced Liver Injury by Regulating the NRF2 Pathway.

Binge drinking patterns easily produce a state of oxidative stress that disturbs liver function. Eventually, this leads to alcoholic liver disease. A safe and effective therapy for alcoholic liver disease remains elusive. Enzyme-treated Z. latifolia extract (ETZL) was studied as a potential agent for treating alcohol-induced liver disease. In addition, its underlying mechanisms were elucidated. In the binge model, ETZL was pretreated with alcohol (5 g/kg) three times at 12-h intervals. Our results showed that ETZL pretreatment decreased the serum levels of ALT, AST, ALP, and TG. ETZL treatment appeared to prevent an increase in hepatic TG and MDA levels, and there was a decrease in total GSH following alcohol treatment. Histopathological examination showed that lipid droplets were significantly reduced in the ETZL group compared to the control group. ETZL also exhibited radical scavenging activity. It significantly reduced t-BHP-induced cytotoxicity and the production of reactive oxygen species (ROS) in HepG2 cells. ETZL also enhanced NRF2 nuclear translocation and increased expression of the downstream target genes HO-1, NQO1, and GCLC as an antioxidant defense. Finally, ETZL treatment significantly reduced cell death. Our study suggests that ETZL ameliorates binge ethanol-induced liver injury by upregulating the antioxidant defense mechanism.

Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway.

Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, β-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

Fermented Rhus Verniciflua Stokes Extract Alleviates Nonalcoholic Fatty Liver through the AMPK/SREBP1/PCSK9 Pathway in HFD-Induced Nonalcoholic Fatty Liver Animal Model

Background: We have previously reported the anti-hepatic lipogenic effect of fermented Rhus verniciflua stokes extract (FRVE) in an oleic-acid-treated HepG2 cell model. Methods: Herein, we advanced our understanding and evaluated the impact of FRVE in HFD-fed C57BL/6 mice using an animal model of nonalcoholic fatty liver disease (NAFLD). Milk thistle extract was used as a positive control to compare the effects of FRVE. Results: FRVE decreased body weight, intra-abdominal fat weight, and liver weight. Furthermore, FRVE decreased HFD-induced elevated serum levels of ALT, AST, TC, and TG, and downregulated the increase in hepatic lipid accumulation and TG levels. FRVE reduced hepatic SREBP-1, PCSK-9, SREBP-2, and ApoB mRNA levels. IHC data showed that FRVE reduced the levels of nucleic SREBP-1, increased the levels of LDLR, and upregulated the expression of p-AMPK. Conclusion: Overall, these results demonstrate the anti-hepatic lipidemic effect of FRVE in an animal model. These findings are consistent with our previous study and strongly suggest that FRVE exerts anti-hepatic lipogenic effects by activating AMPK.

Unacylated Ghrelin Regulates Glucose-Sensitive Neurons Activity and Glycolipid Metabolism via Orexin-A Neurons in the Lateral Hypothalamic Area.

The objective of the study was to investigate the regulatory actions of unacylated ghrelin (UAG) on glucose-sensitive (GS) neurons and glycolipid metabolism in the lateral hypothalamus area (LHA) and its involvement with orexin-A-immunopositive neurons. The effects of UAG administered into the LHA on GS neurons discharges and glycolipid metabolism were detected by single neuron discharge recording, biochemical index analysis and quantitative real-time PCR; the level of c-fos protein in orexin-A-immunopositive neurons was observed using immunofluorescence staining. UAG microinjected into the LHA activated glucose-inhibited neurons, which were partially blocked by pre-administration of anti-orexin-A antibody in the LHA. Furthermore, UAG microinjected into the LHA significantly reduced serum triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol, blood glucose, insulin and hepatic TG levels, while elevated serum high-density lipoprotein cholesterol levels. UAG elevated the mRNA expression of carnitine palmitoyltransferase-1 and reduced the mRNA expression of acetyl-CoA carboxylase-1 in the liver. The above-mentioned effects of UAG were partially blocked by pre-administration of anti-orexin-A antibody. The expressions of orexin-A and c-fos were observed in the LHA. After UAG injection into the LHA, some neurons showed double labeling, and the percentage of double-labeled orexin-A/c-fos neurons in orexin-A-immunopositive neurons increased significantly. UAG in the LHA regulates glycolipid metabolism by activating orexin-A-immunopositive neurons in the LHA.

Lactobacillus Brevis OPK-3 from Kimchi Prevents Obesity and Modulates the Expression of Adipogenic and Pro-Inflammatory Genes in Adipose Tissue of Diet-Induced Obese Mice.

Our previous study reported that lactic acid bacteria (L. brevis OPK-3) isolated from kimchi ameliorated intracellular lipid accumulation in 3T3-L1 adipocyte. The current study explored potential roles of L. brevis OPK-3 (KLAB) on preventing body weight gain and its effect on the inflammatory response of adipose tissue. Male C57BL/6 mice (n = 10) were divided into four groups: normal diet with distilled water (NDC), high-fat diet with distilled water (HDC), high-fat diet with L-ornithine (OTC) or high-fat diet with KLAB. The KLAB supplement resulted in significantly lower body weight, lower epididymal fat tissue mass, and lower serum and hepatic TG levels than the HDC. KLAB supplementation improved serum cytokines, and real-time polymerase chain reaction (PCR) analysis showed significantly lower inflammatory cytokine mRNA levels in epididymal adipose tissue. These results suggest that the administration of KLAB inhibits the induction of inflammation in adipose tissue along with the inhibition of weight gain. Therefore, this study demonstrates the therapeutic and beneficial value of this strain produced during the fermentation of kimchi.

Secoisolariciresinol diglucoside alleviates hepatic lipid metabolic misalignment involving the endoplasmic reticulum-mitochondrial axis.

Secoisolariciresinol diglucoside (SDG) has positive effects on obesity and its complications. We investigated the effects and mechanism of SDG on high-fat and high-fructose diet (HFFD)-induced hepatic lipid metabolic disorders. Supplementation with 40 mg kg-1 d-1 SDG for 12 weeks significantly reduced the body weight and the ratio of liver and adipose tissue to body weight in HFFD-fed mice. Serum and hepatic TG, TC, HDL-C, and LDL-C levels became normalized, and hepatic lipid metabolic disorders lessened because of the downregulation of lipid synthesis genes and upregulation of lipid oxidation genes. SDG also alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction by regulating the ER stress factors Bip, IRE1α, Xbp1, Atf6, Perk, and Chop and mitochondrial function-related genes Cox5b, Cox7a1, Cox8b, and Cycs. Results with HepG2 cells confirmed that SDG regulated lipid metabolic disorders by the ER stress-Ca2+-mitochondrial-associated pathway. Our study provides a strategy for the treatment of obesity and its related comorbidities.

Effect of vitexin on alleviating liver inflammation in a dextran sulfate sodium (DSS)-induced colitis model

As one of commonly used herbs with dual-purpose of drug and food, it has been reported that vitexin has hepatoprotective effects. However, the protective effects of vitexin on colitis-induced liver injury as well as the underlying molecular mechanisms remain unclear. The purpose of the current study was to investigate the effects and mechanisms of vitexin on liver injury induced by acute ulcerative colitis in mice. In this study, the mice model of acute ulcerative colitis was induced by 4 % dextran sodium sulphate (DSS). And then, the degree of liver injury in colitis mice was evaluated, the hepatic ALT, AST, TC and TG levels were measured by specific determination kits, the levels of TNF-α, IL-6 and IL-1β were examined by ELISA, the expressions of TLR4/NF-κB pathway related protein were detected by western blot analysis. The results indicated that hepatic histopathological changes induced by DSS were normalized by vitexin treatment, administration of vitexin decreased the liver levels of ALT and TC in mice with liver injury and reduced the release amounts of DSS-induced pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Furthermore, we found that vitexin inhibited the activation of TLR4/NF-κB signaling pathway induced by DSS. In conclusion, vitexin possess hepatoprotective activities against colitis-induced liver injury, it has potential application prospects in the treatment of liver injury induced by ulcerative colitis.

Collaborative effects of chlorogenic acid and caffeine on lipid metabolism via the AMPKα-LXRα/SREBP-1c pathway in high-fat diet-induced obese mice.

To investigate the mechanism of the combined effects of chlorogenic acid (CGA) and caffeine on lipid metabolism in high-fat diet-induced obese mice, eighty female ICR mice were randomly divided into eight groups and fed with a high-fat diet with/without CGA and/or caffeine for 14 weeks. The combination of CGA and caffeine effectively decreased body weight gain, intraperitoneal adipose tissue weight, serum LDL-c, FFA, TC, TG, leptin, IL-6 concentrations, and hepatic TG and TC levels and increased the serum adiponectin level. The CGA and caffeine combination also promoted the phosphorylation of AMPKα, inhibited the expressions of transcriptional regulators (SREBP-1c and LXRα), and decreased the expressions of FAS and HMGR. Besides, the expressions of ACO, ATGL and HSL were increased by the CGA and caffeine combinations. The results indicated that the combination of CGA and caffeine had anti-obesity effects and regulated lipid metabolism in high-fat diet-induced obese mice via the AMPKα-LXRα/SREBP-1c signaling pathway. Thus, chronic CGA and caffeine intakes may be potent for preventing obesity.

A Porcine Placental Extract Alleviates Lipotoxicity-Induced NASH by Polarizing M2 Macrophages and Attenuating Stellate Cell Activation in Mice

NAFLD is caused by excessive hepatic lipid accumulation and associated with activation of macrophage/Kupffer cells and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we investigated the effect of porcine placental extract (PPE) in a lipotoxicity-induced NASH model. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.1% PPE (CL+0.1%PPE) or 0.3% PPE (CL+0.3%PPE). Liver histology and fibrogenesis were examined. In addition, intrahepatic immune cell numbers were quantified by flow cytometry. After 15 weeks of administration, PPE alleviated lipid accumulation by reducing hepatic TG, TC and NEFA levels, as well as lipid peroxidation, which was assessed by TBARS. PPE improved glucose intolerance and enhanced the insulin signal, assessed by IRβ and Akt phosphorylation, in the liver, which was associated with the attenuation of MAPK (ERK/p38MAPK) and NF-kB activation. Flow cytometry analysis revealed that PPE reduced CD11c+CD206−(M1) by 44.2%, whereas it increased CD11c-CD206+(M2) by 1.4-fold, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. In addition, PPE downregulated LPS-induced M1 marker mRNA expression in isolated murine peritoneal macrophages, but augmented IL-4-induced M2 marker mRNA expression in a dose-dependent manner. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in HSC line. Thus, PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation. Disclosure G. Chen: None. L. Xu: None. N. Nagata: None. M. Nagashimada: None. T. Ota: None.

Chronic exposure to low concentrations of lead induces metabolic disorder and dysbiosis of the gut microbiota in mice

Lead (Pb) is one of the most prevalent toxic, nonessential heavy metals that can contaminate food and water. In this study, effects of chronic exposure to low concentrations of Pb on metabolism and gut microbiota were evaluated in mice. It was observed that exposure of mice to 0.1mg/L Pb, supplied via drinking water, for 15weeks increased hepatic TG and TCH levels. The levels of some key genes related to lipid metabolism in the liver increased significantly in Pb-treated mice. For the gut microbiota, at the phylum level, the relative abundance of Firmicutes and Bacteroidetes changed obviously in the feces and the cecal contents of mice exposed to 0.1mg/L Pb for 15weeks. In addition, 16s rRNA gene sequencing further discovered that Pb exposure affected the structure and richness of the gut microbiota. Moreover, a 1H NMR metabolic analysis unambiguously identified 31 metabolites, and 15 metabolites were noticeably altered in 0.1mg/L Pb-treated mice. Taken together, the data indicate that chronic Pb exposure induces dysbiosis of the gut microbiota and metabolic disorder in mice. CapsuleChronic Pb exposure induces metabolic disorder, dysbiosis of the gut microbiota and hepatic lipid metabolism disorder in mice.

Ether-phosphatidylcholine characterized by consolidated plasma and liver lipidomics is a predictive biomarker for valproic acid-induced hepatic steatosis.

Valproic acid (VPA) is known to induce hepatic steatosis due to mitochondrial toxicity in rodents and humans. In the present study, we administered VPA to SD rats for 3 or 14 days at 250 and 500 mg/kg and then performed lipidomics analysis to reveal VPA-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. VPA induced hepatic steatosis at the high dose level without any degenerative changes in the liver on day 4 (after 3 days dosing) and at the low dose level on day 15 (after 14 days dosing). We compared the plasma and hepatic lipid profiles obtained on day 4 between the VPA-treated and control rats using a multivariate analysis to determine differences between the two groups. In total, 36 species of plasma lipids and 24 species of hepatic lipids were identified as altered in the VPA-treated group. Of these lipid species, ether-phosphatidylcholines (ePCs), including PC(16:0e/22:4) and PC(16:0e/22:6), were decreased in both the plasma and liver from the low dose level on day 4, however, neither an increase in hepatic TG level nor histopathological hepatic steatosis was observed at either dose level on day 4. Hepatic mRNA levels of glycerone-phosphate O-acyltransferase (Gnpat), which is a key enzyme for biosynthesis of ePC, was also decreased by treatment with VPA along with the decrease in ePCs. In conclusion, the changes in ePCs, (PC[16:0e/22:4] and PC[16:0e/22:6]), have potential utility as predictive biomarkers for VPA-induced hepatic steatosis.

PIK3R3 regulates PPAR\u03b1 expression to stimulate fatty acid \u03b2-oxidation and decrease hepatosteatosis

Phosphatidylinositol 3-kinase (PI3K) signaling plays an important role in the regulation of cellular lipid metabolism and non-alcoholic fatty liver disease (NAFLD). However, little is known about the role of the regulatory subunits of PI3K in lipid metabolism and NAFLD. In this study, we characterized the functional role of PIK3R3 in fasting-induced hepatic lipid metabolism. In this study, we showed that the overexpression of PIK3R3 promoted hepatic fatty acid oxidation via PIK3R3-induced expression of PPARα, thus improving the fatty liver phenotype in high-fat diet (HFD)-induced mice. By contrast, hepatic PIK3R3 knockout in normal mice led to increased hepatic TG levels. Our study also showed that PIK3R3-induced expression of PPARα was dependent on HNF4α. The novel PIK3R3-HNF4α-PPARα signaling axis plays a significant role in hepatic lipid metabolism. As the activation of PIK3R3 decreased hepatosteatosis, PIK3R3 can be considered a promising novel target for developing NAFLD and metabolic syndrome therapies.

Structural development of tetrachlorophthalimides as liver X receptor β (LXRβ)-selective agonists with improved aqueous solubility

LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. We have reported a series of tetrachlorophthalimide analogs as an LXRβ-selective agonist. However, they exhibited poor aqueous solubility probably due to its high hydrophobicity and highly rigid and plane structure. In this report, we present further structural development of tetrachloro(styrylphenyl)phthalimides as the LXRβ-selective agonists with improved aqueous solubility.