A promising therapy for fatty liver disease: PCSK9 inhibitors.

BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.

Calpain and Cardiometabolic Diseases.

Calpain is defined as a member of the superfamily of cysteine proteases possessing the CysPC motif within the gene. Calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, including cell migration, apoptosis, and synaptic plasticity. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders. In the context of atherosclerosis, overactivation of conventional calpain attenuates the barrier function of vascular endothelial cells and decreases the immunosuppressive effects attributed to lymphatic endothelial cells. In addition, calpain-6 induces aberrant mRNA splicing in macrophages, conferring atheroprone properties. In terms of diabetes, polymorphisms of the calpain-10 gene can modify insulin secretion and glucose disposal. Moreover, conventional calpain reportedly participates in amino acid production from vascular endothelial cells to induce alteration of amino acid composition in the liver microenvironment, thereby facilitating steatohepatitis. Such multifaceted functionality of calpain underscores its potential as a promising candidate for pharmaceutical targets for the treatment of cardiometabolic diseases. Consequently, the present review highlights the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a characterization of calpains as molecular targets.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Anti-lipid accumulation effects and mechanism of the extract and isolated compounds from Potentilla longifolia.

Potentilla longifolia is effective in the treatment of hepatitis as a Chinese herb. We firstly evaluated the effect of water extract of P. longifolia (WEPL) on mice with nonalcoholic fatty liver disease (NAFLD) induced by high-fat (HF) diet. The results showed that WEPL reduced HF-induced increases of the serum ALT, AST, TG and TC, and reduced lipid drops of liver tissues to a different extent compared with HF group; WEPL dose-dependently promoted the phosphorylation degrees of AMPK and ACC; WEPL decreased significantly genes expressions of SREBP1α, FAS and SCD1 and increased PPARα and CD36. Then three new (1-3) and 13 known compounds (4-16) were firstly-isolated from the 95% ethanol extract of this plant. Further experiments showed that a new compound (ganyearmcaooside C) showed the best inhibitory effect on lipid accumulation in 3 T3-L1 cells such as reducing the accumulation of oil droplets and triglyceride level, showing new drug potential for related diseases.

Saccharified and Fermented Helianthus tuberosus L. Beverage Attenuates High-Fat Diet-Inducible Metabolic Complications in C57BL/6 Mice.

The prevalence of obesity has been recognized as a major public health issue with rapid increase globally. Obesity triggers other metabolic complications, such as diabetes, dyslipidemia, liver diseases, and cardiovascular diseases. Helianthus tuberosus L. (the Jerusalem artichoke) is an important edible plant that may provide health benefits in treating metabolic diseases. In this study, we investigated potential antiobesity effects of saccharified H. tuberosus L. (SH) and its fermented vinegar (fermented H. tuberosus L. [FH]) in a high-fat diet (HFD)-induced obesity murine model. FH exhibited significantly lower pH, Brix, and total sugar content compared with the SH, along with higher radical-scavenging activity. The body weight and adipose tissue weights were significantly decreased with the administration of SH and FH compared with the HFD group. SH and FH groups significantly attenuated hepatomegaly and lipid accumulation. The increased triglyceride (TG) content in obese mice was remarkably lower in the SH and FH groups. SH and FH alleviated serum dyslipidemia and atherogenic risk. Furthermore, expression of adipogenic genes was significantly downregulated after SH and FH supplementation compared with the HFD group. The TG and total cholesterol (TC) content of serum and adipose tissues significantly decreased by SH and FH administration in comparison with the HFD group. Reduced adiposity with SH and FH administration was confirmed by reduced adipocyte size and weight with inhibition of lipoprotein lipase expression. Our study showed that SH and FH, indeed FH was superior to SH, had antiobesity effects by decreasing adiposity, regulating dyslipidemia in systemic tissues, and inhibiting adipogenic gene expression.

Tanshinone IIA and hepatocellular carcinoma: A potential therapeutic drug.

Because of its high prevalence and poor long-term clinical treatment effect, liver disease is regarded as a major public health problem around the world. Among them, viral hepatitis, fatty liver, cirrhosis, non-alcoholic fatty liver disease (NAFLD), and autoimmune liver disease are common causes and inducements of liver injury, and play an important role in the occurrence and development of hepatocellular carcinoma (HCC). Tanshinone IIA (TsIIA) is a fat soluble polyphenol of Salvia miltiorrhiza that is extracted from Salvia miltiorrhiza. Because of its strong biological activity (anti-inflammatory, antioxidant), it is widely used in Asia to treat cardiovascular and liver diseases. In addition, TsIIA has shown significant anti-HCC activity in previous studies. It not only has significant anti proliferation and pro apoptotic properties. It can also play an anti-cancer role by mediating a variety of signal pathways, including phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-B (NF-κB). This review not only reviews the existing evidence and molecular mechanism of TsIIA's anti-HCC effect but also reviews the liver-protective effect of TsIIA and its impact on liver fibrosis, NAFLD, and other risk factors for liver cancer. In addition, we also conducted network pharmacological analysis on TsIIA and HCC to further screen and explore the possible targets of TsIIA against hepatocellular carcinoma. It is expected to provide a theoretical basis for the development of anti-HCC-related drugs based on TsIIA.

Garlic-derived exosomes regulate PFKFB3 expression to relieve liver dysfunction in high-fat diet-fed mice via macrophage-hepatocyte crosstalk.

BACKGROUND: Although macrophage-mediated low-grade chronic inflammation and liver dysfunction have been found to be associated with the development of non-alcoholic fatty (NAFLD) and widely reported, but strategies and drugs targeting macrophages for the treatment of NAFLD are limited. HYPOTHESIS/PURPOSE: Garlic-derived exosomes (GDE) can be useful for NAFLD due to its anti-inflammatory activity. Clarify whether GDE improves liver dysfunction through macrophage-hepatocyte crosstalk. METHODS: GDE was isolated with PEG precipitation and ultracentrifuge. Inflammatory cytokines were detected by qRT-PCR and ELISA. Expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) was determined using qRT-PCR and western blot. Crosstalk between macrophages and hepatocytes was identified through a co-culture experiment. Small RNA sequencing and bioinformatic analysis were used to identify the key element of GDE regulating the expression of PFKFB3 gene. RESULTS: GDE regulated the expression of PFKFB3 to reduce the inflammatory response in LPS-treated differentiated THP-1 macrophages. Data from small RNA sequencing and bioinformatics analysis reveal that miR-396e, one of the most abundant miRNAs of GDE, is the key component to regulate PFKFB3 expression. Mechanistically, miR-396e-mediating PFKFB3 expression plays a crucial role in GDE inhibiting inflammatory response and enhancing lipid metabolism in hepatocytes via the macrophage-hepatocyte crosstalk. Notably, GDE supplementation reduced the inflammatory response and improved liver dysfunction in high-fat diet-fed mice. CONCLUSION: GDE may be useful for improving the symptoms of NAFLD via macrophage-hepatocyte crosstalk and its role in PFKFB3 expression.

In silico profiling of nonsynonymous SNPs of fat mass and obesity-associated gene: possible impacts on the treatment of non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver, or NAFLD, is the most common chronic liver ailment. It is characterized by excessive fat deposition in hepatocytes of individuals who consume little or no alcohol and are unaffected by specific liver damaging factors. It is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease, and sleep apnea. The global burden of NAFLD is increasing at an alarming rate. However, no pharmacologically approved drugs against NAFLD are available owing to their complex pathophysiology. Genome-wide association studies have uncovered SNPs in the fat mass and obesity-associated gene (FTO) that are robustly associated with obesity and higher BMI. The prevalence of NAFLD increases in parallel with the increasing prevalence of obesity. Since FTO might play a crucial role in NAFLD development, the current study identified five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools. METHODS: This study aims to identify potentially deleterious nonsynonymous SNPs (ns-SNPs) employing various in silico tools. Additionally, molecular modeling approaches further studied the structural changes caused by identified SNPs. Moreover, molecular dynamics studies finally investigated the binding potentials of the phytochemicals resveratrol, rosmarinic acid, and capsaicin with different mutant forms of FTO. RESULTS: The current investigation has five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools. The present study identified five nsSNPs of the human gene FTO, Gly103Asp, Arg96Pro, Tyr295Cys, and Arg322Gln, with an apparent connection to the disease condition. Modulation of demethylation activity by phytomolecule scanning explains the hepatoprotective action of molecules. The current investigation also suggested that predicted mutations did not affect the binding ability of three polyphenols: rosamarinic acid, resveratrol, and capsaicin. CONCLUSION: This study showed that the predicted mutations in FTO did not affect the binding of three polyphenols. Thus, these three molecules can significantly aid drug development against FTO and NAFLD.

[Lipid-lowering effect of drug pair Scutellariae Radix-Coptidis Rhizoma based on lipomics].

This study investigated the mechanism of action of Scutellariae Radix-Coptidis Rhizoma(SR-CR) in intervening in non-alcoholic fatty liver disease(NAFLD) in rats based on lipidomics. Thirty-six SD rats were divided into a control group, a model group, SR-CR groups of different doses, and a simvastatin group, with six rats in each group. Rats in the control group were fed on a normal diet, while those in the remaining groups were fed on a high-lipid diet. After four weeks of feeding, drug treatment was carried out and rats were sacrificed after 12 weeks. Serum liver function and lipid indexes were detected using kits, and the pathomorphology of liver tissues was evaluated by hematoxylin-eosin(HE) staining and oil red O staining. Changes in lipid levels in rats were detected using the LC-MS technique. Differential lipid metabolites were screened by multivariate statistical analysis, and lipid metabolic pathways were plotted. The changes in lipid-related protein levels were further verified by Western blot. The results showed that compared with the control group, the model group showed increased levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.01), and decreased levels of γ-glutamyl transferase(γ-GT) and high-density lipoprotein cholesterol(HDL-c)(P<0.01), which were significantly recovered by the intervention of SR-CR. HE staining and oil red O staining showed that different doses of SR-CR could reverse the steatosis in the rat liver in a dose-dependent manner. After lipidomics analysis, there were significant differences in lipid metabolism between the model group and the control group, with 54 lipids significantly altered, mainly including glycerolipids, phosphatidylcholine, and sphingolipids. After administration, 44 differential lipids tended to normal levels, which indicated that SR-CR groups of different doses significantly improved the lipid metabolism level in NAFLD rats. Western blot showed that SR-CR significantly decreased TG-synthesis enzyme 1(DGAT1), recombinant lipin 1(LPIN1), fatty acid synthase(FASN), acetyl-CoA carboxylase 1(ACC1), and increased the phosphorylation level of ACC1. These changes significantly decreased the synthesis of TG and increased the rate of its decomposition, which enhanced the level of lipid metabolism in the body and finally achieved the lipid-lowering effect. SR-CR can improve NAFLD by inhibiting the synthesis of fatty acids and TG.

Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases.

Mitochondria are double-membrane organelles that play a role in ATP synthesis, calcium homeostasis, oxidation-reduction status, apoptosis, and inflammation. Several human disorders have been linked to mitochondrial dysfunction. It has been found that traditional therapeutic herbs are effective on alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) which are leading causes of liver cirrhosis and hepatocellular carcinoma. The generation of reactive oxygen species (ROS) in response to oxidative stress is caused by mitochondrial dysfunction and is considered critical for treatment. The role of oxidative stress, lipid toxicity, and inflammation in NAFLD are well known. NAFLD is a chronic liver disease that commonly progresses to cirrhosis and chronic liver disease, and people with obesity, insulin resistance, diabetes, hyperlipidemia, and hypertension are at a higher risk of developing NAFLD. NAFLD is associated with a number of pathological factors, including insulin resistance, lipid metabolic dysfunction, oxidative stress, inflammation, apoptosis, and fibrosis. As a result, the improvement in steatosis and inflammation is enough to entice researchers to look into liver disease treatment. However, antioxidant treatment has not been very effective for liver disease. Additionally, it has been suggested that the beneficial effects of herbal medicines on immunity and inflammation are governed by various mechanisms for lipid metabolism and inflammation control. This review provided a summary of research on herbal medicines for the therapeutic implementation of mitochondria-mediated ROS production in liver disease as well as clinical applications through herbal medicine. In addition, the pathophysiology of common liver disorders such as ALD and NAFLD would be investigated in the role that mitochondria play in the process to open new therapeutic avenues in the management of patients with liver disease.

Therapeutic potential of traditional Chinese medicine for the treatment of NAFLD: A promising drug Potentilla discolor Bunge.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.

Chinese Herbal Medicine for Type 2 Diabetes Mellitus With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Objectives: To evaluate the efficacy and safety of Chinese herbal medicine (CHM) for type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD) with current evidence. Methods: This study was registered in PROSPERO as CRD42021271488. A literature search was conducted in eight electronic databases from inception to December 2021. The primary outcomes were lipid indices and liver functions, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine transaminase (ALT), and aspartate transaminase (AST). Review Manager 5.2 and Stata v14.0 were applied for analysis. Results: The research enrolled 18 RCTs with 1,463 participants. Results showed CHM combined with western medicine (WM) was more effective than WM alone in TG (weighted mean differences (WMD) = -0.35.95% confidence interval (CI) [-0.51, -0.19], p < 0.0001), TC (WMD = -0.58.95%CI [-0.80, -0.36], p < 0.00001), LDL-C (WMD = -0.37, 95%CI [-0.47, -0.26], p < 0.00001), HDL-C (WMD = 0.20, 95%CI [0.10, 0.29], p < 0.0001), ALT (WMD = -4.99, 95%CI [-6.64, -3.33], p < 0.00001), AST (WMD = -4.76, 95%CI [-6.35, -3.16], p < 0.00001), homeostatic model assessment of insulin resistance (WMD = -1.01, 95%CI [-1.22, -0.79], p < 0.00001), fasting blood glucose (WMD = -0.87, 95%CI [-1.13, -0.61], p < 0.00001), 2-h postprandial glucose (WMD = -1.45.95%CI [-2.00, -0.91], p < 0.00001), body mass index (WMD = -0.73.95%CI [-1.35, -0.12], p = 0.02), and overall effective rate (risk ratio (RR) = 1.37.95%CI [1.29, 1.46], p < 0.00001). Conclusion: The CHM in combination with WM seems to be more beneficial in T2DM with NAFLD patients in improving lipid and glucose metabolism, liver function, and insulin resistance as well as improving overall efficiency and reducing body weight. Given the poor quality of reports from these studies and uncertain evidence, these findings should be interpreted cautiously. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271488, identifier CRD42021271488.

Mega-Dose Vitamin C Ameliorates Nonalcoholic Fatty Liver Disease in a Mouse Fast-Food Diet Model.

In previous studies, the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD) has been recognized. However, the specific therapeutic strategies or drugs have not been discovered. Vitamin C is a water-soluble antioxidant and is a cofactor in many important biosynthesis pathways. Recently, many researchers have reported that the mega-dose vitamin C treatment had positive effects on various diseases. However, the precise relationship between mega-dose vitamin C and NAFLD has not been completely elucidated. This study has been designed to discover the effects of mega-dose vitamin C on the progression of NAFLD. Twelve-week-old wild-type C57BL6 mice were fed chow diets and high-fat and high-fructose diet (fast-food diet) ad libitum for 11 weeks with or without of vitamin C treatment. Vitamin C was administered in the drinking water (1.5 g/L). In this study, 11 weeks of the mega-dose vitamin C treatment significantly suppressed the development of nonalcoholic steatohepatitis (NASH) independently of the catabolic process. Vitamin C supplements in fast-food diet fed mice significantly decreased diet ingestion and increased water intake. Histopathological analysis revealed that the mice fed a fast-food diet with vitamin C water had a mild renal injury suggesting osmotic nephrosis due to fructose-mediated purine derivatives. These data suggest that the mega-dose vitamin C treatment suppresses high-fructose-diet-mediated NAFLD progression by decreasing diet ingestion and increasing water intake.

Effects of Lingonberry (Vaccinium vitis-idaea L.) Supplementation on Hepatic Gene Expression in High-Fat Diet Fed Mice.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide in association with Western-style diet and increasing obesity. Lingonberry (Vaccinium vitis-idaea L.) is rich in polyphenols and has been shown to attenuate adverse metabolic changes in obese liver. This paper investigated the effects of lingonberry supplementation on hepatic gene expression in high-fat diet induced obesity in a mouse model. C57BL/6N male mice were fed for six weeks with either a high-fat (HF) or low-fat (LF) diet (46% and 10% energy from fat, respectively) or HF diet supplemented with air-dried lingonberry powder (HF + LGB). HF diet induced a major phenotypic change in the liver, predominantly affecting genes involved in inflammation and in glucose and lipid metabolism. Lingonberry supplementation prevented the effect of HF diet on an array of genes (in total on 263 genes) associated particularly with lipid or glucose metabolic process (such as Mogat1, Plin4, Igfbp2), inflammatory/immune response or cell migration (such as Lcn2, Saa1, Saa2, Cxcl14, Gcp1, S100a10) and cell cycle regulation (such as Cdkn1a, Tubb2a, Tubb6). The present results suggest that lingonberry supplementation prevents HF diet-induced adverse changes in the liver that are known to predispose the development of NAFLD and its comorbidities. The findings encourage carrying out human intervention trials to confirm the results, with the aim of recommending the use of lingonberries as a part of healthy diet against obesity and its hepatic and metabolic comorbidities.

Design of Hepatic Targeted Drug Delivery Systems for Natural Products: Insights into Nomenclature Revision of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-dysfunction-associated fatty liver disease (MAFLD), affects a quarter of the worldwide population. Natural products have been extensively utilized in treating NAFLD because of their distinctive advantages over chemotherapeutic drugs, despite the fact that there are no approved drugs for therapy. Notably, the limitations of many natural products, such as poor water solubility, low bioavailability in vivo, low hepatic distribution, and lack of targeted effects, have severely restricted their clinical application. These issues could be resolved via hepatic targeted drug delivery systems (HTDDS) that boost clinical efficacy in treating NAFLD and decrease the adverse effects on other organs. Herein an overview of natural products comprising formulas, single medicinal plants, and their crude extracts has been presented to treat NAFLD. Also, the clinical efficacy and molecular mechanism of active monomer compounds against NAFLD are systematically discussed. The targeted delivery of natural products via HTDDS has been explored to provide a different nanotechnology-based NAFLD treatment strategy and to make suggestions for natural-product-based targeted nanocarrier design. Finally, the challenges and opportunities put forth by the nomenclature update of NAFLD are outlined along with insights into how to improve the NAFLD therapy and how to design more rigorous nanocarriers for the HTDDS. In brief, we summarize the up-to-date developments of the NAFLD-HTDDS based on natural products and provide viewpoints for the establishment of more stringent anti-NAFLD natural-product-targeted nanoformulations.

Ameliorative Effect of Myricetin on Nonalcoholic Fatty Liver Disease in ob/ob Mice.

Obesity, insulin resistance, and oxidative stress are important risk factors for nonalcoholic fatty liver disease (NAFLD). This study aimed at determining the beneficial effects of myricetin against NAFLD in ob/ob mice. C57BL/6-Lepob/ob mice (n = 21) were fed an AIN-93G diet (ob/ob control group) or diet containing 0.04% (low myricetin; LMTN group) or 0.08% (high myricetin; HMTN group) myricetin, and lean heterozygous littermates (lean control group, n = 7) were fed AIN-93G diet for 10 weeks. HMTN consumption significantly lowered serum glucose levels and homeostasis model assessment for insulin resistance values in ob/ob mice. In addition to reducing serum triglyceride (TG) and cholesterol levels, HMTN significantly decreased total hepatic lipid and TG levels partly through downregulation of carbohydrate response element-binding protein and sterol regulatory element-binding protein 1c expression. The reduction in the levels of hepatic thiobarbituric acid reactive substances by HMTN likely resulted from the elevation of nuclear factor erythroid-2-related factor 2 expression. Tumor necrosis factor-α and monocyte chemoattractant protein 1 expressions were reduced by LMTN and HMTN, and HMTN also decreased interleukin-6 expression. These results suggest that myricetin has beneficial effects against NAFLD by regulating the expression of transcription factors of hepatic lipid metabolism, the antioxidant system, and pro-inflammatory cytokines.

Phytotherapy as Multi-Hit Therapy to Confront the Multiple Pathophysiology in Non-Alcoholic Fatty Liver Disease: A Systematic Review of Experimental Interventions.

Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is a metabolic condition distinguished by fat deposition in the hepatocytes. It has a prevalence of about 25% worldwide and is associated with other conditions such as diabetes mellitus, obesity, hypertension, etc. Background and Objectives: There is currently no approved drug therapy for NAFLD. Current measures in the management of NAFLD include lifestyle modification such as an increase in physical activity or weight loss. Development of NAFLD involves a number of parallel hits: including genetic predisposition, insulin resistance, disordered lipid metabolism, mitochondrial dysfunction, lipotoxicity, oxidative stress, etc. Herbal therapy may have a role to play in the treatment of NAFLD, due to their numerous bioactive constituents and the multiple pharmacological actions they exhibit. Therefore, this systematic review aims to investigate the potential multi-targeting effects of plant-derived extracts in experimental models of NAFLD. Materials and Methods: We performed a systematic search on databases and web search engines from the earliest available date to 30 April 2021, using relevant keywords. The study included articles published in English, assessing the effects of plant-derived extracts, fractions, or polyherbal mixtures in the treatment of NAFLD in animal models. These include their effects on at least disordered lipid metabolism, insulin resistance/type 2 diabetes mellitus (T2DM), and histologically confirmed steatosis with one or more of the following: oxidative stress, inflammation, hepatocyte injury, obesity, fibrosis, and cardiometabolic risks factors. Results: Nine articles fulfilled our inclusion criteria and the results demonstrated the ability of phytomedicines to simultaneously exert therapeutic actions on multiple targets related to NAFLD. Conclusions: These findings suggest that herbal extracts have the potential for effective treatment or management of NAFLD.

Microcystin Toxicokinetics, Molecular Toxicology, and Pathophysiology in Preclinical Rodent Models and Humans.

Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression.

Herbal therapy for ameliorating nonalcoholic fatty liver disease via rebuilding the intestinal microecology.

The worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, and this metabolic disorder has been recognized as a severe threat to human health. A variety of chemical drugs have been approved for treating NAFLD, however, they always has serious side effects. Chinese herbal medicines (CHMs) have been widely used for preventing and treating a range of metabolic diseases with satisfactory safety and effective performance in clinical treatment of NAFLD. Recent studies indicated that imbanlance of the intestinal microbiota was closely associated with the occurrence and development of NAFLD, thus, the intestinal microbiota has been recognized as a promising target for treatment of NAFLD. In recent decades, a variety of CHMs have been reported to effectively prevent or treat NAFLD by modulating intestinal microbiota to further interfer the gut-liver axis. In this review, recent advances in CHMs for the treatment of NAFLD via rebuilding the intestinal microecology were systematically reviewed. The key roles of CHMs in the regulation of gut microbiota and the gut-liver axis along with their mechanisms (such as modulating intestinal permeability, reducing the inflammatory response, protecting liver cells, improving lipid metabolism, and modulating nuclear receptors), were well summarized. All the knowledge and information presented here will be very helpful for researchers to better understand the applications and mechanisms of CHMs for treatment of NAFLD.

Liver tissue microbiota in nonalcoholic liver disease: a change in the paradigm of host-bacterial interactions.

Nonalcoholic fatty liver disease (NAFLD) pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors, the genetic variance of the nuclear and mitochondrial genome, associated phenotypic traits, and the yet not fully explored interactions with epigenetic and other environmental factors, including the microbiome. Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD, the precise mechanisms that explain the variability of the histological phenotypes are not fully understood. Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis (NASH) provided clues on the role of the fecal microbiome in the disease pathogenesis. Nevertheless, the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity, including liver inflammation, ballooning of hepatocytes, and fibrosis. The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein. Therefore, not only microbes would become entrapped in the complex liver anatomy but, more importantly, bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response. Hence, the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a "gut-centric" to a "liver-centric" approach. Here, we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH. Besides, we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.