The increased prevalence of hyperlipidemia significantly affects human health worldwide. Although drug treatment is very effective, the harm to the human body cannot be ignored. Improvement of lipid metabolism by natural medicinal and food homologous products is an effective approach to ameliorate hyperlipidemia and it has gradually become a research focus. In this research, we adopted HepG2 cell models and high-fat-diet-fed C57BL/6j mouse models to explore the effect of hawthorn total flavonoids (HTF) on hyperlipidemia. Moreover, we utilized western blot and gut microbiota analysis to elucidate the specific mechanism of HTF's influence on hyperlipidemia.

We found that HTF significantly alleviated hyperlipidemia and its complications, as manifested by reduced body weight gain and fat accumulation, and improved the disorder of intestinal microorganisms. HTF protected the liver, reducing aspartate transaminase and lactate dehydrogenase levels, and ameliorating inflammatory infiltration. Fat droplet amounts and necrotic cell numbers in liver cells were also decreased. Mechanistically, HTF promoted AMP-activated protein kinase phosphorylation, inhibited sterol regulatory element binding protein 1c expression, downregulating the expression of lipid synthesis-related proteins (acetyl CoA carboxylase, fatty acid synthase, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), thus suppressing liver lipid synthesis. HTF also functioned as a natural peroxisome proliferator-activated receptor α (PPARα) agonist. Activated PPARα enhanced mitochondrial oxidation and lipid consumption via upregulating carnitine palmitoyltransferase 1A. Peroxisome proliferator-activated receptor-γ coactivator expression was also elevated, activating mitochondrial activity, increasing cholesterol 7α-hydroxylase activity and cholesterol consumption, and reducing blood lipids. Additionally, HTF regulated intestinal flora abundance, restored the ratio of Firmicutes to Bacteroidetes, balanced gut-liver axis crosstalk, and alleviated hyperlipidemia.

The results demonstrated that HTF alleviated the pathological symptoms caused by hyperlipidemia, and had a certain protective effect on the liver. HTF also stimulated the lipid metabolism pathway and accelerated lipid consumption. © 2025 Society of Chemical Industry.

Astilbin (ATB), a natural flavonoid compound with anti-inflammatory bioactivities, can be isolated from Smilax china L., which has been used in traditional Chinese medicine to treat pelvic inflammatory disease (PID) (including endometritis). Our previous studies reported that flavonoids from Smilax china rhizome (FSCR) have therapeutic effects in rats with PID. However, the effects of ATB, the main active component of FSCR, against endometritis remain unknown.

We aim to investigate the role of ATB on endometritis induced by lipopolysaccharide (LPS) in rats and elucidate the mechanisms underlying anti-inflammatory action of ATB on LPS-stimulated endometrial epithelial cells (EECs).

The effects and action mechanisms of ATB on LPS-induced endometritis in rats and LPS-induced EECs were systematically assessed using H&E staining, immunohistochemistry, ELISA, RT-PCR, western blotting, immunofluorescence, molecular docking and siRNA knockdown technology.

ATB significantly alleviated typical uterine pathological damages in endometritis, decreased inflammatory cytokine levels in both serum and uterus, and also inhibited the excessive release of inflammatory cytokines in EECs induced by LPS. Mechanistically, ATB markedly upregulated PPAR-γ levels and suppressed the overexpression of TLR4 and IL-6R proteins and their downstream signals, MyD88, and phosphorylation of NF-κB P65, JAK2, and STAT3, in vivo. Further, the effects of ATB on PPAR-γ protein expression, and NF-κB and STAT3 signalling activation in LPS-induced EECs were consistent with the results of in vivo experiments. Furthermore, both PPAR-γ-specific siRNA transfection and a selective PPAR-γ antagonist abolished ATB-induced inhibition of NF-κB and STAT3 signalling activation and production of inflammatory cytokines. Molecular docking and in vitro experiments further proved that ATB can target PPAR-γ binding.

Overall, our results demonstrated that ATB can significantly inhibit endometritis in rats, presumably through interfering with NF-κB and STAT3 signal transduction in a PPAR-γ-dependent manner, blocking the positive feedback between NF-κB and STAT3 signalling. Our findings provide new evidences for developing the ATB, the main compound identified from FSCR, as a potential therapeutic agent for endometritis.

Non-alcoholic steatohepatitis (NASH) is an important component of non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide. Gentianella turkestanorum (Gands.) Holub is a traditional monk medicine used for the treatment of hepatitis, and total iridoid glycosides from it (GTI) are the main active substances in the treatment of liver diseases. However, the role and mechanism of GTI in NASH remain unclear.

This study aimed to assess the effectiveness of GTI in treating NASH induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and clarify the underlying mechanisms.

The efficacy of GTI against aberrant lipid metabolism was evaluated in vitro in L02 cells and in vivo in a C57BL/6 NASH mouse model. Based on these evaluations in L02 cells and C57BL/6 NASH mice, swertiamarine (SWT) was identified as a potential active component of GTI. RNA sequencing was performed to further explore the therapeutic effects of SWT on the liver. The analysis identified the targeting of key signalling pathways PPARα, p53, and MAPKp38. The therapeutic efficacy of SWT was validated using siRNAs or agonists against PPARα or MAPKp38.

In this study, a combination of ex vivo and in vivo experiments was used to ascertain the mitigating effects of GTI and SWT on NASH. The efficacy was correlated with PPARα, p53, and MAPKp38 pathways, as determined by RNA sequencing. In vitro and in vivo experiments demonstrated that SWT influenced the expression of PPARα, p-p53, Caspase3, Bax, Bcl2, and p-MAPKp38. However, the efficacy of SWT is counteracted when PPARα is inhibited with siRNAs or MAPKp38 is activated with DHC in vitro.

SWT, a potential active ingredient in GTI, may have a therapeutic effect on abnormal L02 lipid metabolism and NASH in mice by affecting the PPARα/MAPK/p53 signalling pathway. Therefore, SWT holds potential clinical application in the prevention and treatment of NASH.

Hyperlipidemia is regarded as one of the crucial factors leading to atherosclerosis and other cardiovascular diseases. Gut microbiota plays an important role in regulating host lipid metabolism. Nevertheless, the exact mechanisms behind this remain unclear.

In the present study, a hyperlipidemic zebrafish model was established using a high-cholesterol diet (HCD) to evaluate the anti-hyperlipidemic effects of Lactobacillus fermentum E15 (L. fermentum E15).

Results showed that L. fermentum E15 effectively reduced lipid accumulation in the blood vessels and liver of HCD-fed zebrafish larvae. Meanwhile, L. fermentum E15 improved abnormal lipid levels, and normalized liver enzyme activity. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis revealed that L. fermentum E15 downregulated the expression of sterol regulatory element-binding factor (SREBP-1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and fatty acid synthase (Fasn), while upregulated peroxisome proliferator-activated receptor-alpha (PPAR-α). Additionally, metabolomic analysis revealed that L. fermentum E15 produced a series of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid, and isovaleric acid. Notably, isovaleric acid contributed to the reduction of lipid droplet accumulation in the liver and blood vessels of HCD-fed zebrafish larvae. In contrast, blocking G-protein coupled receptor 43 (GPR43) with pertussis toxin (PTX) abolished the effects of L. fermentum E15 and isovaleric acid on reducing lipid accumulation in HCD-fed zebrafish larvae. RT-qPCR results further suggested that both L. fermentum E15 and isovaleric acid promoted the expression of GPR43 and leptin A, which was inhibited by PTX.

These findings suggested that L. fermentum E15 alleviates HCD-induced hyperlipidemia by activating GPR43 through SCFAs.

Polygonum cyrtonema Hua is a kind of traditional Chinese botanic drug. Modern pharmacological research has confirmed that Polygonum cyrtonema Hua is able to alleviate nonalcoholic fatty liver disease, but the precise mechanism requires further investigation. This study investigated the protective effects and underlying mechanisms of Polygonatum cyrtonema ethanol extract (PCE) against Non-alcoholic steatohepatitis (NASH) in mice.

UHPLC-MS/MS was utilized to analyze the metabolites of PCE. The NASH mouse model was establishment in C57BL/6J mice via high-fat diet (HFD) feeding for 12 weeks, and from the 9th week, mice were gavaged with PCE (100, 300, and 900 mg/kg/day), simvastatin (4 mg/kg) or saline. One hand, liver injury was assessed by serum enzymes, biochemistry, and histopathology; On the other hand, RNA-seq, qPCR, and Western blot were employed to investigate the related molecular mechanisms.

211 metabolites were identified through UHPLC-MS/MS analysis. PCE ameliorated HFD induced liver injury and improved hepatocellular degeneration and steatosis in a dose-dependent way. PCE restored the expression of AMPK, SIRT1, SREBP1 and PPAR-α both in mRNA and protein levels. RNAseq identified unique gene expression profiles in response to high-fat diet (HFD) compared to the PCE treatments. HFD-induced DEGs were attenuated or abolished following PCE treatments. Ingenuity pathway analysis of RNA-seq data revealed key canonical pathways and upstream molecules regulated by PCE.

Our findings confirm the ability of PCE in alleviating NASH and underscores AMPK/SIRT1 pathway as a potential theraputic target for NASH treatment.

As a critical disease usually infected by Staphylococcus aureus, with a worldwide effect on dairy animals, subclinical mastitis is characterized by persistence and treatment resistance. During mastitis, the blood-milk barrier (BMB)'s integrity is impaired, resulting in pathogen invasion and milk quality decline. In this study, it was found that ginsenoside Rg1 (Rg1), a natural anti-inflammatory and antioxidant compound derived from ginseng, inhibited the onset of tight junction (TJ) dysfunction and ameliorated lipoteichoic acid (LTA)-induced BMB disruption inside and outside the organisms. According to subsequent mechanistic studies, Rg1 inhibited excessive autophagy and inactivated the NLRP3 inflammasome by blockading ROS generation, thereby alleviating TJ dysfunction. Peroxisome proliferator-activated receptor gamma (PPARγ) was identified as a potential target of Rg1 by means of molecular docking plus network pharmacology analysis. Furthermore, it was demonstrated that Rg1 inhibited the oxidative stress levels by activating PPARγ, and regulating the upstream autophagy-related AMPK/mTOR signaling pathway, thus decreasing excessive in vivo and in vitro autophagy. The ROS/autophagy/NLRP3 inflammasome axis was identified as a promising target for treating subclinical bovine mastitis in this study. In conclusion, Rg1 is proven to alleviate BMB disruption by activating PPARγ to inhibit oxidative stress and subsequent excessive autophagy in the case of subclinical bovine mastitis.

The initial stage of alcoholic liver disease (ALD) is hepatic steatosis. Recent studies have highlighted a possible role for Apoptosis-stimulating protein 2 of p53 (ASPP2) in regulating hepatic lipid metabolism in nonalcoholic fatty liver (NAFLD). However, whether ASPP2 regulates alcohol-induced lipid accumulation and its mechanisms remain unclear. To explore that, we establish an alcoholic liver injury model in vivo and in vitro. The clinical specimens were collected from liver tissues of patients with alcoholic liver disease. Lipid metabolism was detected by HE staining, oil red O staining and qPCR; and ASPP2-peroxisome proliferator-activated receptor γ (PPARγ) signaling pathways were detected by western blot and immunohistochemical staining. We found that both ASPP2 and PPARγ expression increased in patients and mouse models with ALD. We also discovered the reduction of ASPP2 significantly inhibited the expression of PPARγ and alleviated alcohol-induced hepatic lipid accumulation and liver injury in vivo and in vitro. Mechanistically, the PPARγ agonist reversed the protective effect of ASPP2 downregulation on hepatic steatosis and liver injury, while the opposite results were observed using PPARγ inhibitor. In conclusion, ASPP2 exacerbates ethanol-induced lipid accumulation and hepatic injury by upregulating the PPARγ signaling pathway, thus promoting the occurrence and development of ALD.

With the rising popularity of pet cats as companion animals, the survival of newborn kittens is often threatened by factors such as inadequate nursing, maternal behavior and blood incompatibility. These challenges require the use of milk replacers for nurturing. To investigate the effects that feeding kittens with an experimental milk replacer (EMR) have on growth and development, intestinal microbiota, immune response and nutrient metabolism, 12 British shorthair kittens were randomly divided into two groups after nursing for the first week of life. Kittens were fed queen's milk or EMR, whereby kittens fed queen's milk served as the control (CON) group. The findings revealed that the CON group exhibited superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) (p < 0.01) on day 7. However, the EMR group had better growth performance during the later stage of the experiment (p < 0.05); the immunocompetence and antioxidant capacity of the EMR group were not significantly different from those of the CON group in the middle and late stages of the experiment, and the mean values of all the indexes were slightly better than those of the control group. Sequencing of the 16S rRNA gene in microbiota demonstrated that EMR increased the colonization of bacterial genera, including Lachnospiraceae, Enterococcus, Rothia and Ligilactobacillus. Compared to the CON group, acetate acid (p < 0.05), propionate acid (p < 0.01) and total SCFAs (p < 0.01) in the EMR group were significantly increased. Moreover, the intake of the EMR resulted in the production of distinct metabolites implicated in the metabolism of lipids and amino acids, among other nutrients, thus invigorating the associated metabolic pathways. These results elucidate the impact of administering a milk replacer on gastrointestinal health and nutrient assimilation in kittens. The study provides insights into the use of milk powder alternatives and sets the stage for future research on the formulation and effectiveness of kitten milk replacers.

Wang's metabolic formula (WMF) is a traditional Chinese medicine formula developed under the guidance of Professor Kungen Wang. WMF has been clinically utilized for several years. However, the therapeutic mechanism of WMF in treating metabolic-associated fatty liver disease (MAFLD) remains unclear. In this study, we performed phytochemical analysis on WMF using LC-MS. To study the role of WMF in MAFLD, we orally administered WMF (20.6 g/kg) to male MAFLD mice induced by a high-cholesterol high-fat diet (HCHFD). Then pathological, biochemical, and metabolomic analyses were performed. The main components of WMF are chlorogenic acid, geniposide, albiflorin, paeoniflorin, and calycosin-7-O-glucoside. MAFLD mice treated with WMF exhibited significant improvements in obesity, abnormal lipid metabolism, inflammation, and liver pathology. WMF decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels in the serum of MAFLD mice while increasing high-density lipoprotein cholesterol (HDL-c) levels. WMF lowered liver TG levels and inflammatory factors (IL-1β, IL-6, TNF-α, and NF-κB). Metabolomic analysis of the liver annotated 78 differentially regulated metabolites enriched in four pathways: glycerophospholipid metabolism, retinol metabolism, PPAR signaling pathway, and choline metabolism. Western blot experiments showed that WMF increased the expression of PPAR-α, PPAR-β, and RXR in the liver while decreasing the expression of RAR. The study demonstrates that WMF has a solid preventive and therapeutic effect on MAFLD. The anti-inflammatory and regulation of abnormal liver metabolism activities of WMF involve retinol metabolism and the PPAR signaling pathway.

Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD.

SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg-1·d-1) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin-eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels.

The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid.

Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

Flubendiamide (FLU), a widely used diamide insecticide, has been observed to potentiate adipogenesis in 3T3-L1 preadipocytes in vitro. Whether exposure to FLU disrupts hepatic lipid homeostasis in mammals and induces visceral obesity, however, remains unclear. The aim of this study was to assess the effects of FLU when administered orally to male C57BL/6J mice under normal diet (ND) and high-fat diet (HFD) conditions. FLU accumulated at higher levels in the tissues of the HFD group than those of the ND group, indicating that an HFD contributed to the accumulation of lipophilic pesticides in vivo. Notably, FLU (logP = 4.14) is highly lipophilic and easily accumulates in fat. Exposure to FLU had opposing effects on the lipid metabolism of the liver in the ND and HFD groups. Liver triacylglycerol levels in the ND group were reduced, while those in the HFD group were increased, resulting in more severe hepatic steatosis. More lipid accumulation was also observed in HepG2 cells exposed to FLU. Changes in hepatic lipid deposition in vivo occurred as the enhanced transcriptional regulation of the genes involved in lipid uptake, de novo lipogenesis, and fatty acid β-oxidation (FAO). Moreover, an excessive increase in FAO caused oxidative stress, which in turn exacerbated the inflammation of the liver. This study revealed the disruptive effect of FLU exposure on hepatic lipid homeostasis, which may facilitate the triggering of nonalcoholic fatty liver disease in HFD-fed mice.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored.

In the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique.

The results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load.

There is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem that affects more than a quarter of the population. The development of this disease is correlated with metabolic dysfunctions that lead to lipid accumulation in the liver. Pesticides are one of etiologies that support NAFLD establishment. Therefore, the effects of the insecticide fipronil on the lipid metabolism of the human hepatic cell line, HepG2, was investigated, considering its widespread use in field crops and even to control domestic pests. To address the goals of the study, biochemical, cellular, and molecular analyses of different concentrations of fipronil in cell cultures were investigated, after 24 h of incubation. Relevant metabolites such as triglycerides, glucose levels, β-oxidation processes, and gene expression of relevant elements correlated with lipid and metabolism of xenobiotics were investigated. The results suggested that at 20 μM, the pesticide increased the accumulation of triglycerides and neutral lipids by reducing fatty acid oxidation and increasing de novo lipogenesis. In addition, changes were observed in genes that control oxidative stress and the xenobiotic metabolism. Together, the results suggest that the metabolic changes caused by the insecticide fipronil may be deleterious if persistent, favoring the establishment of hepatic steatosis.

The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases.

A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them.

From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

Obesity has been recognized as a worldwide public health crisis, this is accompanied by dysregulation of the intestinal microbiota and upregulation of liver steatosis and adipose inflammation. Synbiotic as a novel alternative therapy for obesity have recently gained much attention.

This study innovatively research the anti-obesity properties of a newly synbiotic composed of Lactobacillus acidophilus, Bifidobacterium infantis and konjac glucomannan oligosaccharides.

The synbiotic treatment can reduce body weight, fat mass, blood sugar, liver steatosis and adipose inflammation in obesity mice fed by high-fat diet (HFD). Meanwhile, synbiotic treatment activated brown adipose tissue and improve energy, glucose and lipid metabolism. In addition, synbiotic treatment not solely enhanced the protection of intestinal barrier, but also ameliorated gut microbiota dysbiosis directly by enhancing beneficial microbes and reducing potentially harmful bacteria. Furthermore, the microbiome phenotype and functional prediction showed that synbiotic treatment can improve the gut microbiota functions involving inflammatory state, immune response, metabolism and pathopoiesia.

The synbiotic may be an effective candidate treatment strategy for the clinical prevention and treatment of obesity and other associated metabolic diseases such as hyperlipidemia, nonalcoholic fatty liver diseases by alleviating inflammatory response, regulating energy metabolism and maintaining the balance of intestinal microecology.

Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin that causes oxidative damage in various organs. At present, the research studies on AFB1 are primarily focused on its effects on the terrestrial environment and animals. However, its toxicity mechanism in aquatic environments and aquatic animals has not been largely explored. Thus, in this study, zebrafish was used as a model to study the toxicity mechanism of AFB1 on the liver of developing larvae. The results showed that AFB1 exposure inhibited liver development and promoted fat accumulation in the liver. Transcriptome sequencing analysis showed that AFB1 affected liver redox metabolism and oxidoreductase activity. KEGG analysis showed that AFB1 inhibited the expression of gsto1, gpx4a, mgst3a, and idh1 in the glutathione metabolizing enzyme gene pathway, resulting in hepatic oxidative stress. At the same time, AFB1 also inhibited the expression of acox1, acsl1b, pparα, fabp2, and cpt1 genes in peroxidase and PPAR metabolic pathways, inducing hepatic steatosis and lipid droplet accumulation. Antioxidant N-Acetyl-l-cysteine (NAC) preconditioning up-regulated gsto1, gpx4a and idh1 genes, and improved the AFB1-induced lipid droplet accumulation in the liver. In summary, AFB1 induced hepatic oxidative stress and steatosis, resulting in abnormal liver fat metabolism and accumulation of cellular lipid droplets. NAC could be used as a potential preventative drug to improve AFB1-induced fat accumulation.

Perfluorobutane sulfonates (PFBS) have garnered extensive utilization because of their distinctive physicochemical properties. The liver acts as a key target organ for toxicity within the body and is vital for regulating metabolic processes, particularly lipid metabolism. However, there is currently a significant research gap regarding the influences of PFBS on hepatic lipid metabolism, especially in individuals with different dietary statuses. Here, the objective of this research was to examine the effects of PFBS on hepatic function under different dietary conditions. The results suggested that the levels of liver injury biomarkers were significantly upregulated, e.g., transaminase (GPT, GOT), while liver lipid levels were downregulated after exposure to PFBS at concentration of 50 μg/L for 42 days. Moreover, restricted diet further intensified the adverse effects of PFBS on the liver. Metabolomics analysis identified significant alterations in lipid-related metabolites in PFBS-induced hepatotoxicity, PFBS exposure induced a decrease in lysophosphatidylethanolamine and lysophosphatidylcholine. PFBS exposure caused an increase in aldosterone and prostaglandin f2alpha under restricted diet. In PFBS treatment group, histidine metabolism, beta-alanine metabolism, and arginine biosynthesis were the main pathway for PFBS toxicity. Aldosterone-regulated sodium reabsorption as a vital factor in inducing PFBS toxicity in the RD-PFBS treatment group. The analysis of 16S rRNA sequencing revealed that exposure to PFBS resulted in imbalance of gut microbial communities. PFBS exposure induced a decrease in Akkermansia and Lactobacillus, but an increase in Enterococcus. PFBS exposure caused the abundance of Lachnospiraceae_NK4A136_group was significantly elevated under restricted diet. Additionally, disruptions in the expression of genes involved in lipid production and consumption may significantly contribute to lipid imbalance in the liver. This study underscores the importance of recognizing the harmful impact of PFBS on liver function, along with the biotoxicity of contaminant influenced by dietary habits.

Chronic liver disease (CLD) constitutes a growing global health issue, with no effective treatments currently available. Oxidative stress closely interacts with other cellular and molecular processes to trigger stress pathways in different hepatic cells and fuel the development of liver fibrosis. Therefore, inhibition of reactive oxygen species (ROS)-mediated effects and modulation of major antioxidant responses to counteract oxidative stress-induced damage have emerged as interesting targets to prevent or ameliorate liver injury. Although many preclinical studies have shown that dietary supplements with antioxidant properties can significantly prevent CLD progression in animal models, this strategy has not proved effective to significantly reduce fibrosis when translated into clinical trials. Novel and more specific therapeutic approaches are thus required to alleviate oxidative stress and reduce liver fibrosis. We have reviewed the relevant literature concerning the crucial role of alterations in redox homeostasis in different hepatic cell types during the progression of CLD and discussed current pharmacological approaches to ameliorate fibrosis by reducing oxidative stress focusing on selective modulation of enzymatic oxidant sources, antioxidant systems and ROS-mediated pathogenic processes.

Insulin resistance, as a common pathological process of many metabolic diseases, including diabetes and obesity, has attracted much attention due to its relevant influencing factors. To date, studies have mainly focused on the shared mechanisms between mitochondrial stress and insulin resistance, and they are now being pursued as a very attractive therapeutic target due to their extensive involvement in many human clinical settings. In view of the complex pathogenesis of diabetes, natural drugs have become new players in diabetes prevention and treatment because of their wide targets and few side effects. In particular, plant phenolics have received attention because of their close relationship with oxidative stress. In this review, we briefly review the mechanisms by which mitochondrial stress leads to insulin resistance. Moreover, we list some cytokines and genes that have recently been found to play roles in mitochondrial stress and insulin resistance. Furthermore, we describe several natural drugs that are currently widely used and give a brief overview of their therapeutic mechanisms. Finally, we suggest possible ideas for future research related to the unique role that natural drugs play in the treatment of insulin resistance through the above targets.

As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has been reported to partially prevent olanzapine-induced dyslipidemia and obesity through a combination therapy, although the underlying epigenetic mechanisms are still not known. Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPARγ pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.

Atherosclerosis, a chief pathogenic factor of cardiovascular disease, is associated with many factors including inflammation, dyslipidemia, and oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are widely expressed with tissue- and cell-specificity. They control multiple genes that are involved in lipid metabolism, inflammatory response, and redox homeostasis. Given the diverse biological functions of PPARs, they have been extensively studied since their discovery in 1990s. Although controversies exist, accumulating evidence have demonstrated that PPAR activation attenuates atherosclerosis. Recent advances are valuable for understanding the mechanisms of action of PPAR activation. This article reviews the recent findings, mainly from the year of 2018 to present, including endogenous molecules in regulation of PPARs, roles of PPARs in atherosclerosis by focusing on lipid metabolism, inflammation, and oxidative stress, and synthesized PPAR modulators. This article provides information valuable for researchers in the field of basic cardiovascular research, for pharmacologists that are interested in developing novel PPAR agonists and antagonists with lower side effects as well as for clinicians.

Adaptor proteins represent key signalling molecules involved in regulating immune responses. The host's innate immune system recognizes pathogens via various surface and intracellular receptors. Adaptor molecules are centrally involved in different receptor-mediated signalling pathways, acting as bridges between the receptors and other molecules. The presence of adaptors in major signalling pathways involved in the pathogenesis of various chronic inflammatory diseases has drawn attention toward the role of these proteins in such diseases. In this review, we summarize the importance and roles of different adaptor molecules in macrophage-mediated signalling in various chronic disease states. We highlight the mechanistic roles of adaptors and how they are involved in protein-protein interactions (PPI) via different domains to carry out signalling. Hence, we also provide insights into how targeting these adaptor proteins can be a good therapeutic strategy against various chronic inflammatory diseases.

Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.

The study aimed to explore the association of serum 25(OH)D₃ and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and to determine whether the effect of vitamin D (VD) is mediated by activation of the peroxisome proliferator-activated receptor α (PPARα) pathway.

The study contained a case-control study, in vivo and in vitro experiments. A case-control study was conducted to compare serum parameters between NAFLD patients and controls and to evaluate the association of 25(OH)D₃ and NAFLD. In vivo study, male Wistar rats were randomly divided into control and model groups, fed a standard chow diet and a high-fat diet (HFD), respectively, for 7 weeks to generate an NAFLD model. Then, the rats were treated with VD and a PPARα antagonist (MK886) for 7 weeks. Tissue and serum were collected and assessed by biochemical assays, morphological analysis, histological analysis, and western blot analysis. In vitro, HepG2 cells were incubated with oleic acid (OA) to induce steatosis, which was evaluated by staining. HepG2 cells were pretreated with MK886 followed by calcitriol treatment, and differences in lipid metabolism-related proteins were detected by western blot.

NAFLD patients were characterized by impaired liver function, dyslipidemia, and insulin resistance. Serum 25(OH)D₃ was negatively associated with alanine aminotransferase (ALT) in NAFLD. VD deficiency was a risk factor for patients with no advanced fibrosis. Adequate VD status (25(OH)D₃ >20 ng/mL) had a protective effect in patients after adjustment for confounding variables. NAFLD rats showed hyperlipidemia with severe hepatic steatosis, systematic inflammation, and lower serum 25(OH)D₃. VD treatment ameliorated hepatic steatosis both in NAFLD rats and OA-induced HepG2 cells. Further, MK886 inhibited the anti-steatosis effect of VD.

The study revealed that an adequate VD level may act as a protective factor in NAFLD and that VD may alleviate hepatic steatosis via the PPARα signaling pathway.

Bee bread (BB) has traditionally been used as a dietary supplement to treat liver problems. This study evaluated the therapeutic effects of Heterotrigona itama BB from Malaysia on obesity-induced hepatic lipid metabolism disorder via the regulation of the Keap1/Nrf2 pathway. Male Sprague Dawley rats were fed with either a normal diet or high-fat diet (HFD) for 6 weeks to induce obesity. Following 6 weeks, obese rats were treated either with distilled water (OB group), BB (0.5 g/kg body weight/day) (OB + BB group) or orlistat (10 mg/kg body weight/day) (OB + OR group) concurrent with HFD for another 6 weeks. BB treatment suppressed Keap1 and promoted Nrf2 cytoplasmic and nuclear translocations, leading to a reduction in oxidative stress, and promoted antioxidant enzyme activities in the liver. Furthermore, BB down-regulated lipid synthesis and its regulator levels (SIRT1, AMPK), and up-regulated fatty acid β-oxidation in the liver of obese rats, being consistent with alleviated lipid levels, improved hepatic histopathological changes (steatosis, hepatocellular hypertrophy, inflammation and glycogen expression) and prevented progression to non-alcoholic steatohepatitis. These results showed the therapeutic potentials of H. itama BB against oxidative stress and improved lipid metabolism in the liver of obese rats possibly by targeting the Keap1/Nrf2 pathway, hence proposing its role as a natural supplement capable of treating obesity-induced fatty liver disease.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing and lifestyle interventions to treat this disease by addressing the underlying metabolic syndrome are often limited. Many pharmacological interventions are being studied to slow or even reverse NAFLD progression. This review for hepatologists aims to provide an updated understanding of the pathogenesis of NAFLD, current recommended therapies, and the most promising treatment options that are currently under development.

Insulin resistance (IR) is a risk factor for metabolic disorders and neurodegeneration. Peroxisome proliferator-activated receptor (PPAR) agonists have been proven to mitigate the neuronal pathology associated with IR. However, the synergetic efficacy of these agonists is yet to be fully described. Hence, we aimed to investigate the efficacy of PPARα/γ agonists (fenofibrate and pioglitazone) on a high-fat diet (HFD) and streptozotocin (STZ)-induced hippocampal neurodegeneration. Male Wistar rats (200 ± 25 mg/body weight [BW]) were divided into five groups. The experimental groups were fed on an HFD for 12 weeks coupled with 5 days of an STZ injection (30 mg/kg/BW, i.p) to induce IR. Fenofibrate (FEN; 100 mg/kg/BW, orally), pioglitazone (PIO; 20 mg/kg/BW, orally), and their combination were administered for 2 weeks postinduction. Behavioral tests were conducted, and blood was collected to determine insulin sensitivity after treatment. Animals were killed for assessment of oxidative stress, cellular morphology characterization, and astrocytic evaluation. HFD/STZ-induced IR increased malondialdehyde (MDA) levels and decreased glutathione (GSH) levels. Evidence of cellular alterations and overexpression of astrocytic protein was observed in the hippocampus. By contrast, monotherapy of FEN and PIO increased the GSH level (p < 0.05), decreased the MDA level (p < 0.05), and improved cellular morphology and astrocytic expression. Furthermore, the combined treatment led to improved therapeutic activities compared to monotherapies. In conclusion, FEN and PIO exerted a therapeutic synergistic effect on HFD/STZ-induced IR in the hippocampus.

Nonalcoholic fatty liver disease (NAFLD) represents a class of disorders including hepatic steatosis, steatohepatitis, and liver fibrosis. Previous research suggested that xyloketal B (Xyl-B), a marine-derived natural product, could attenuate the NAFLD-related lipid accumulation. Herein, we investigated the protective mechanism of Xyl-B in a high-fat diet (HFD) mice fatty liver model by combining a quantitative proteomic approach with experimental methods. The results showed that the administration of Xyl-B (20 and 40 mg·kg^-1·day^-1, ip) ameliorated the hepatic steatosis in HFD mice. Proteomic profiling together with bioinformatics analysis highlighted the upregulation of a cluster of peroxisome proliferator-activated receptor-α (PPARα) downstream enzymes mainly related to fatty acid oxidation (FAO) as key changes after the treatment. These changes were subsequently confirmed by bioassays. Moreover, further results showed that the expression levels of PPARα and PPARγ coactivator-1α (PGC1α) were increased after the treatment. The related mode-of-action was confirmed by PPARα inhibition. Furthermore, we evaluated the PPARα-mediated anti-inflammatory and antifibrosis effect of Xyl-B in methionine-choline-deficient (MCD) mice hepatitis and liver fibrosis models. According to the results, the histological features were improved, and the levels of inflammatory factors, adhesion molecules, as well as fibrosis markers were decreased after the treatment. Collectively, these results indicated that Xyl-B ameliorated different phases of NAFLD through activation of the PPARα/PGC1α signaling pathway. Our findings revealed the possible metabolism-regulating mechanism of Xyl-B, broadened the application of xyloketal family compounds, and may provide a new strategy to curb the development of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a general term for a series of liver diseases including simple steatosis, non-alcoholic steatohepatitis, liver fibrosis, which is closely related to metabolic syndrome. The pathogenesis of NAFLD is relatively complex, which has gradually changed from the previous 'two-hit' hypothesis to the current "multiple hits" hypothesis. However, there is currently no approved treatment for NAFLD in clinic, highlighting the urgent need for drug development. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily, whose different subtypes have been proved to regulate different stages of NAFLD, thus becoming promising drug targets for NAFLD. As important sources of drug development, natural products have been proven to treat NAFLD through multiple pathways and multiple targets. In this paper, we outline the regulatory role of PPARs in NAFLD, and summarize some natural products that target PPARs to ameliorate NAFLD, in order to provide reference for drug development of NAFLD.

Di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is a ubiquitous environmental pollutant that can disrupt endocrine function. Epidemiological studies suggest that chronic exposure to DEHP in the environment is associated with the prevalence of childhood allergic diseases; however, the underlying causal relationship and immunological mechanism remain unclear. This study explored the immunomodulatory effect of DEHP on allergic lung inflammation, while particularly focusing on the impact of DEHP and its metabolite on dendritic cell differentiation and activity of peroxisome proliferator-activated receptor gamma (PPARγ). The results showed that exposure to DEHP at a human tolerable daily intake dose exacerbated allergic lung inflammation in mice. Ex vivo flow cytometric analysis revealed that DEHP-exposed mice displayed a significantly decreased number of CD8α⁺ dendritic cells (DCs) in spleens and DC progenitors in the bone marrow, as well as, less interleukin-12 production in splenic DCs and increased T helper 2 polarization. Pharmacological experiments showed that mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP, significantly hampered the differentiation of CD8α⁺ DCs from Fms-like tyrosine kinase 3 ligand-differentiated bone marrow culture, by modulating PPARγ activity. These results suggested that chronic exposure to DEHP at environmentally relevant levels, promotes allergic lung inflammation, at least in part, by altering DC differentiation through the MEHP-PPARγ axis. This study has crucial implications for the interaction(s) between environmental pollutants and innate immunity, with respect to the development of allergic asthma.

Hepatic oval cells have strong proliferation and differentiation capabilities and are activated when chronic liver injury occurs or when liver function is severely impaired. Peroxisome proliferation-activated receptors (PPARs) are ligand-dependent, sequence-specific nuclear transcription factors. PPARγ is closely related to liver diseases (such as liver cancer, liver fibrosis and non-alcoholic fatty liver disease). As the main effector downstream of the Hippo signaling pathway, YAP can activate the hepatic progenitor cell program, and different expression or activity levels of YAP can determine different liver cell fates. We found that troglitazone (TRO), a classic PPARγ activator, can inhibit the growth of hepatic oval cells, and flow cytometry results showed that TRO inhibited the growth of WB-F344 cells by arresting the cells in the G_0/1 phase. Western blot results also confirmed changes in G_0/1 phase-related protein expression. Further experiments showed that PPARγ agonists induced hepatic oval cell proliferation inhibition and cell cycle G_0/1 phase arrest through the Hippo/YAP pathway. Our experiment demonstrated, for the first time, the relationship between PPARγ and the Hippo/YAP pathway in liver oval cells and revealed that PPARγ acts as a negative regulator of liver regeneration by inhibiting the proliferation of oval cells.

Obesity is a major risk factor for metabolic dysfunction such as non-alcoholic fatty liver disease (NAFLD). The NAFLD spectrum ranges from simple steatosis, to steatohepatitis, fibrosis, and cirrhosis. The aim of this study is to characterize the grade of steatosis being associated with overnutrition and obesity, both at the level of single hepatocyte and whole liver, and to correlate it with the hepatocyte/liver stiffness and dysfunction. For the in vivo study, 60 subjects were enrolled and grouped based on the stage of liver steatosis/fibrosis according to biochemical analyses, liver ultrasonography (USG) and acoustic radiation force impulse shear wave elastography (ARFI-SWE). For single hepatocyte analyses we employed in vitro models of moderate and severe steatosis on which to assess the single cell biomechanics by Single Cell Force Spectroscopy (SCFS) and Quantitative Phase Microscopy (QPM). Results show that in vivo liver stiffness depends mainly on the extent of fat accumulation and not on fibrosis. These results parallel the in vitro observations showing that hepatocyte stiffness and dysfunction increase with increasing fat accumulation and lipid droplet enlargement. Our findings indicate that the extent of steatosis markedly affects the biomechanical properties of both liver and single hepatocytes thus proving insights about the role of modulation of liver/hepatocyte elasticity as a physical mechanism transducing the obesity-dependent excess of plasmatic lipids towards liver steatosis and dysfunction.

3-tert-Butyl-4-hydroxyanisole (3-BHA), one of the widely used food antioxidants, has been found to act as a potential obesogen by promoting adipogenesis in vitro and inducing white adipose tissue development in vivo. Whether 3-BHA-induced visceral obesity was accompanied by a disruption of hepatic lipid homeostasis in mammals remained unclear. In this study, we evaluated the effect of 3-BHA on the development of nonalcoholic fatty liver disease (NAFLD) in male C57BL/6J mice. After 18 weeks of oral administration of 10 mg/kg 3-BHA, the mice fed with a high-fat diet (HFD) had higher hepatic triglyceride concentrations (0.32 mg/mg protein) and severer steatosis (1.57 for the NAFLD score) than the control ones. The in vivo hepatic lipid deposition disturbed by 3-BHA was transcriptionally regulated by the genes involved in lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export. The in vitro studies further confirmed that 24 h of exposure to 50 μM 3-BHA could induce intracellular oleic acid (OA) uptake and triglyceride accumulation (1.5-fold of the OA control) in HepG2 cells. Lipidomic analysis indicated the perturbation of 3-BHA in the levels of 30 lipid species related to sphingolipids, glycerophospholipids, and glycerolipids under HFD conditions. The findings herein first revealed the disruption effect of 3-BHA on hepatic lipid homeostasis, thus exacerbating the development of HFD-induced NAFLD.

Tebuconazole (TEB), a triazole fungicide, is frequently applied to agriculture for the increase of food production. Although TEB causes liver toxicity, its effects on cellular lipid accumulation are rarely investigated. Therefore, this study aimed to study the effects of TEB on lipid metabolism and accumulation in HepG2 cells. HepG2 cells were exposed to 0-320 µM TEB for 1-24 h. TEB (20-80 µM, 24 h)-treated cells showed lipid accumulation. Further, TEB (20-80 µM, 1-12 h) increased the nuclear translocation of peroxisome proliferator-activated receptors and the expression of lipid uptake and oxidation-related markers such as cluster of differentiation 36, fatty acid transport protein (FATP) 2, FATP5, and carnitine palmitoyltransferase 1. Oxidative stress levels in TEB-treated cells (20-80 µM, 24 h) were higher, compared to those in the control. TEB (20-80 µM, 24 h) also induced the loss of mitochondrial membrane potential and lower levels of microsomal triglyceride transfer protein in the cells. Thus, TEB can induce lipid accumulation by altering the expression of lipid-metabolizing molecules and can therefore impair lipid metabolism. Our data suggest that human exposure to TEB may be a risk factor for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.

Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ.

Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ.

Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ-deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked.

In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.

In order to explore the mechanism of liver injury induced by florfenicol (FFC) in broilers. Sixty broilers were randomly divided into 2 groups: control group: normal drinking water and feed were given every d; FFC group: tap water containing FFC (0.15g/L) was given every d and feed was taken freely; each group was given 5 dd of continuous medication and feed was taken freely. The results showed that compared with the control group, FFC could significantly inhibit the weight gain of broilers (P < 0.05), and significantly inhibit the expression of CYP1A1 and CYP2H1 in liver tissue (P < 0.05). It was found that the expression of genes related to the effect of cytochrome P450 on the metabolism of exogenous substances, the peroxisome proliferators-activated receptors signal pathway, peroxisome pathway and glutathione metabolic pathway in the liver of broilers. The results of qPCR of UDP glucuronosyltransferase family 2A1 (UGT2A1), glutathione S-transferase-like 2 (GSTAL2), hematopoietic prostaglandin D synthase (HPGDS), glutathione S-transferase theta 1(GSTT1), isocitrate dehydrogenase (NADP(+)) 1 (IDH1), acyl-CoA oxidase 2 (ACOX2), fatty acid binding protein 1 (FABP1), adenylosuccinate lyase (ADSL), and phosphoribosyl aminoim idazolesuccino carboxamide synthase (PAICS) genes which were randomly selected from the most significant genes were consistent with those of RNA-seq. The results showed that FFC can affect the drug metabolism and lipid synthesis in the liver of broiler, thus impairing the normal function of liver and the growth and development of broiler.

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder in both China and worldwide. It ranges from simple steatosis and progresses over time to nonalcoholic steatohepatitis (NASH), advanced liver fibrosis, cirrhosis, or hepatocellular carcinoma(HCC). Furthermore, NAFLD and its complications impose a huge health burden to society. The microbiota is widely connected and plays an active role in human physiology and pathology, and it is a hidden 'organ' in determining the state of the host, in terms of homeostasis, or disease. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptorsuperfamily and can regulate multiple pathways involved in metabolism, and serve as effective targets forthe treatment of many types of metabolic syndromes, including NAFLD. The purpose of this review is to integrate related articles on gut microbiota, PPARs and NAFLD, and present a balanced overview on how the microbiota can possibly influence the development of NAFLD through PPARs.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in the development of various tumor types. However, its role in hepatocellular carcinoma (HCC) remains unclear. Multiple databases including The Cancer Genome Atlas, Gene Expression Omnibus and Kaplan-Meier plotter were used for bioinformatics analysis of the PPARγ gene or protein. Immunohistochemical labeling of tumor and adjacent normal tissues obtained from 125 patients with HCC was performed to analyze the relationship between PPARγ expression and overall survival (OS) rate. PPARγ was evaluated using functional enrichment analyses and Lasso regression was used to conduct a dimensionality reduction analysis of 43 clinical factors for HCC. An OS prognostic nomogram was then established using seven independent risk factors screened via Lasso regression. PPARγ expression in HCC tumor tissues was higher compared with that in normal liver tissues, and its high expression was associated with poor prognosis, as indicated by bioinformatics analysis. However, opposite results were obtained using the clinical specimens. Functional enrichment analysis indicated that PPARγ was enriched in the 'fatty acid metabolism' pathway. Lasso regression identified seven clinical factors associated with prognosis, including Tumor-Node-Metastasis stage, grade, vascular invasion, α fetoprotein, carbohydrate antigen 199, γ-glutamyl transpeptidase and the PPARγ protein. These seven clinical factors were to construct an OS prognostic nomogram. Overall, PPARγ was highly expressed in the livers of patients with HCC and can be included in an OS prognostic nomogram. However, the factors underlying the differential association of PPARγ expression with HCC prognosis in different datasets should be further investigated.