Mechanisms of ferroptosis in nonalcoholic fatty liver disease and therapeutic effects of traditional Chinese medicine: a review.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)), and lobular inflammation and hepatocyte damage (which characterize nonalcoholic steatohepatitis (NASH) are found in most patients). A subset of patients will gradually develop liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma, which is a deadly disease that threatens human life worldwide. Ferroptosis, a novel nonapoptotic form of programmed cell death (PCD) characterized by iron-dependent accumulation of reactive oxygen radicals and lipid peroxides, is closely related to NAFLD. Traditional Chinese medicine (TCM) has unique advantages in the prevention and treatment of NAFLD due to its multicomponent, multipathway and multitarget characteristics. In this review, we discuss the effect of TCM on NAFLD by regulating ferroptosis, in order to provide reference for the further development and application of therapeutic drugs to treat NAFLD.

Huanglian-Hongqu herb pair improves nonalcoholic fatty liver disease via NF-κB/NLRP3 pathway in mice: network pharmacology, molecular docking and experimental validation.

The Huanglian-Hongqu herb pair (HH) is a carefully crafted traditional Chinese herbal compound designed to address disorders related to glucose and lipid metabolism. Its primary application lies in treating hyperlipidemia and fatty liver conditions. This study explored the potential mechanism of HH in treating non-alcoholic fatty liver disease (NAFLD) through network pharmacology, molecular docking, and in vivo animal experiments. Ultrahigh performanceliquid chromatography-quadrupole/orbitrapmass spectrometry (UPLC-Q-TOF-MS) was employed to identify the chemical composition of HH. Network pharmacology was used to analyze the related signaling pathways affected by HH. Subsequently, the prediction was verified by animal experiment. Finally, we identified 29 components within HH. Network pharmacology unveiled interactions between HH and 153 NAFLD-related targets, highlighting HH's potential to alleviate NAFLD through NF-κB signaling pathway. Molecular docking analyses illuminated the binding interactions between HH components and key regulatory proteins, including NF-κB, NLRP3, ASC, and Caspase-1. In vivo experiments demonstrated that HH alleviated NAFLD by reducing serum and liver lipid levels, improving liver function, and lowering inflammatory cytokine levels in the serum. Moreover, HH administration downregulated mRNA and protein levels of the NF-κB/NLRP3 pathway. In conclusion, our findings demonstrated that HH has potential therapeutic benefits in ameliorating NAFLD by targeting the NF-κB/NLRP3 pathway, facilitating the broader application of HH in the field of NAFLD.

Liver Lipidomics Analysis Revealed the Protective mechanism of Zuogui Jiangtang Qinggan Formula in type 2 diabetes mellitus with non-alcoholic fatty liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic steatosis, a hallmark of non-alcoholic fatty liver disease (NAFLD), represents a significant global health issue. Liver lipidomics has garnered increased focus recently, highlighting Traditional Chinese Medicine's (TCM) role in mitigating such conditions through lipid metabolism regulation. The Zuogui Jiangtang Qinggan Formula (ZGJTQGF), a longstanding TCM regimen for treating Type 2 Diabetes Mellitus (T2DM) with NAFLD, lacks a definitive mechanism for its lipid metabolism regulatory effects. AIM OF THE STUDY: This research aims to elucidate ZGJTQGF's mechanism on lipid metabolism in T2DM with NAFLD. MATERIALS AND METHODS: The study, utilized db/db mice to establish T2DM with NAFLD models. Evaluations included Hematoxylin-Eosin (HE) and Oil Red O stainedstaining of liver tissues, alongside biochemical lipid parameter analysis. Liver lipidomics and Western blotting further substantiated the findings, systematically uncovering the mechanism of action mechanism. RESULTS: ZGJTQGF notably reduced body weight, and Fasting Blood Glucose (FBG), enhancing glucose tolerance in db/db mice. HE, and Oil Red O staining, complemented by biochemical and liver lipidomics analyses, confirmed ZGJTQGF's efficacy in ameliorating liver steatosis and lipid metabolism anomalies. Lipidomics identified 1571 significantly altered lipid species in the model group, primarily through the upregulation of triglycerides (TG) and diglycerides (DG), and the downregulation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Post-ZGJTQGF treatment, 496 lipid species were modulated, with increased PC and PE levels and decreased TG and DG, showcasing significant lipid metabolism improvement in T2DM with NAFLD. Moreover, ZGJTQGF's influence on lipid synthesis-related proteins was observed, underscoring its anti-steatotic impact through liver lipidomic alterations and offering novel insights into hepatic steatosis pathogenesis. CONCLUSIONS: Liver lipidomics analysis combined with protein verification further demonstrated that ZGJTQGF could ameliorate the lipid disturbance of TG, DG, PC, PE in T2DM with NAFLD, as well as improve fatty acid and cholesterol synthesis and metabolism through De novo lipogenesis pathway.

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.

Independent associations of serum calcium with or without albumin adjustment and serum phosphorus with nonalcoholic fatty liver disease: results from NHANES 1999-2018.

Background: The associations of serum calcium and phosphorus with nonalcoholic fatty liver disease (NAFLD) remain unclear. In addition, there may be an effect of albumin correction on the association between serum calcium and NAFLD. We aimed to explore these relationships in the National Health and Nutrition Examination Survey (NHANES). Methods: Eligible adult individuals from NHANES 1999-2018 were recruited for the study. We explored the associations of serum calcium, albumin-adjusted serum calcium, and serum phosphorus with NAFLD in multivariable-adjusted regression models. In addition, restricted cubic spline (RCS), stratified analysis, and multiple sensitivity analyses were used for further elaboration. Results: The study sample consisted of 20,900 participants, with an observed NAFLD prevalence of 44.65%. Fully adjusted models indicated that serum calcium was inversely associated with NAFLD (odds ratio [OR] and 95% confidence interval [CI] = 0.70 (0.62, 0.78), p<0.0001), whereas albumin-adjusted serum calcium was positively associated with NAFLD (OR and 95% CI=1.59 (1.41, 1.79), p<0.0001). RCS modeling indicated that serum calcium without and with albumin adjustment was linearly(p nonlinear = 0.083) and nonlinearly (p nonlinear < 0.0001) associated with NAFLD, respectively, whereas serum phosphorus showed a U-shaped relationship with NAFLD(p nonlinear < 0.0001). Gender is a significant influence in all associations, and other variables may also have an effect. Sensitivity analyses indicated that these associations were independent of additional significant confounders. Conclusion: Serum calcium and phosphorus were significantly associated with the development of NAFLD. These findings suggest the potential clinical significance of serum calcium/phosphorus and albumin levels in individuals at high risk for NAFLD. Our study supports the potential role of serum calcium/phosphorus homeostasis in the pathophysiology of NAFLD and could serve as NAFLD-related biomarkers.

Smilax China L. polysaccharide prevents HFD induced-NAFLD by regulating hepatic fat metabolism and gut microbiota.

BACKGROUND: The increasing incidence of nonalcoholic fatty liver disease (NAFLD) has urged the development of new therapeutics. NAFLD is intimately linked to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for preventing NAFLD. Smilax china L. polysaccharide (SCP) possesses excellent hepatoprotective and anti-inflammatory activity. However, its protective effects on NAFLD remains unclear. PURPOSE: The goal of this study was to explore the protective effects of SCP on high-fat diet (HFD)-induced NAFLD mice by regulating hepatic fat metabolism and gut microbiota. METHODS: Extraction and isolation from Smilax china L. rhizome to obtain SCP. C57BL/6 J mice were distributed to six groups: Control (normal chow diet), HFD-fed mice were assigned to HFD, simvastatin (SVT), and low-, medium-, high-doses of SCP for 12 weeks. The body, liver, and different adipose tissues weights were detected, and lipids in serum and liver were assessed. RT-PCR and Western blot were used to detect the hepatic fat metabolism-related genes and proteins. Gut microbiota of cecum contents was profiled through 16S rRNA gene sequencing. RESULTS: SCP effectively reversed HFD-induced increase weights of body, liver, and different adipose tissues. Lipid levels of serum and liver were also significantly reduced after SCP intervention. According to the results of RT-PCR and western blot analysis, SCP treatment up-regulated the genes and proteins related to lipolysis were up-regulated, while lipogenesis-related genes and proteins were down-regulated. Furthermore, the HFD-induced dysbiosis of intestinal microbiota was similarly repaired by SCP intervention, including enriching beneficial bacteria and depleting harmful bacteria. CONCLUSION: SCP could effectively prevent HFD-induced NAFLD, might be considered as a prebiotic agent due to its excellent effects on altering hepatic fat metabolism and maintaining gut microbiota homeostasis.

Natural Products in the Modulation of Farnesoid X Receptor Against Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with a high prevalence and increasing economic burden, but official medicine remains unavailable. Farnesoid X receptor (FXR), a nuclear receptor member, is one of the most promising drug targets for NAFLD therapy that plays a crucial role in modulating bile acid, glucose, and lipid homeostasis, as well as inhibits hepatic inflammation and fibrosis. However, the rejection of the FXR agonist, obecholic acid, by the Food and Drug Administration for treating hepatic fibrosis raises a question about the functions of FXR in NAFLD progression and the therapeutic strategy to be used. Natural products, such as FXR modulators, have become the focus of attention for NAFLD therapy with fewer adverse reactions. The anti-NAFLD mechanisms seem to act as FXR agonists and antagonists or are involved in the FXR signaling pathway activation, indicating a promising target of FXR therapeutic prospects using natural products. This review discusses the effective mechanisms of FXR in NAFLD alleviation, and summarizes currently available natural products such as silymarin, glycyrrhizin, cycloastragenol, berberine, and gypenosides, for targeting FXR, which can facilitate development of naturally targeted drug by medicinal specialists for effective treatment of NAFLD.

Docosahexaenoic Acid Modulates Nonalcoholic Fatty Liver Disease by Suppressing Endocannabinoid System.

SCOPE: Endocannabinoid signaling regulates energy homeostasis, and is tightly associated with nonalcoholic fatty liver disease (NAFLD). The study previously finds that supplementation of docosahexaenoic acid (DHA) has superior function to ameliorate NAFLD compared with eicosapentaenoic acid (EPA), however, the underlying mechanism remains elusive. The present study aims to investigate whether DHA intervention alleviates NAFLD via endocannabinoid system. METHODS AND RESULTS: In a case-control study, the serum endocannabinoid ligands in 60 NAFLD and 60 healthy subjects are measured. Meanwhile, NAFLD model is established in mice fed a high-fat and -cholesterol diet (HFD) for 9 weeks. DHA or EPA is administrated for additional 9 weeks. Serum primary endocannabinoid ligands, namely anandamide (AEA) and 2-arachidoniylglycerol (2-AG), are significantly higher in individuals with NAFLD compared with healthy controls. NAFLD model shows that serum 2-AG concentrations and adipocyte cannabinoid receptor 1 expression levels are significantly lower in DHA group compared with HFD group. Lipidomic and targeted ceramide analyses further confirm that endocannabinoid signaling inhibition has exerted deletion of hepatic C16:0-ceramide contents, resulting in down-regulation of de novo fatty acid synthesis and up-regulation of fatty acid ß-oxidation related protein expression levels. CONCLUSIONS: This work elucidates that DHA has improved NAFLD by suppressing endocannabinoid system.

Vine tea total flavonoids activate the AMPK/mTOR pathway to amelioration hepatic steatosis in mice fed a high-fat diet.

Vine tea (Ampelopsis grossedentata), a traditional Chinese tea, is rich in flavonoids with various biological activities. Our study found that Vine tea total flavonoids (TFs) treatment reduced the body mass and blood lipid levels and improved the hepatic tissue morphology in mice fed the high-fat diet (HFD). In vivo, TF treatment activated the hepatic adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, initiated autophagy, and regulated the expression levels of proteins for lipid metabolism in those HFD-fed mice. In vitro, TF treatment dramatically reduced the lipid droplets and triacylglycerol content in HepG2 and L02 cells treated with oleic acid (OA). These were associated with the activation of the AMPK/mTOR pathway and autophagy initiation in OA-treated hepatocytes. This phenotype was abolished in the presence of 3-methyladenine, an autophagy inhibitor. Our results indicated that the TF activation of AMPK/mTOR leads to the stimulation of autophagy and a decrease in the buildup of intracellular lipids in hepatocytes, showing the potential of TF as a therapeutic agent for nonalcoholic fatty liver disease. PRACTICAL APPLICATION: Vine tea, a tea drink, has been consumed by Chinese folk for over a thousand years. The result of this study will provide evidence that vine tea total flavonoids have potential use as a functional material for the prevention and amelioration of nonalcoholic fatty liver disease.

Integration of pharmacodynamics and metabolomics to reveal rhubarb anthraquinone protection against nonalcoholic fatty liver disease rat model.

OBJECTIVES: The objective of the present study was to investigate the effect of Rhubarb anthraquinone (RA) on a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rat model, and explore potential biomarker and metabolic pathways by using the metabolomics method. MATERIALS AND METHODS: We established HFD rats as the NAFLD model. Forty Sprague-Dawley rats were randomly divided into a control group, model group, RA low-dose group, RA medium-dose group, and RA high-dose group, and evaluated the protective effect of RA on NAFLD by detecting biochemical indicators of serum and pathological changes of liver tissue. Investigating potential biomarkers and metabolic pathways connected with RA's protective effects against NAFLD by UHPLC-Q-TOF-MS untargeted metabolomics. RESULTS: The results showed that RA significantly reversed the increase of TG, TC, ALT, AST, and ALP (P < .05), the decrease of HDL-C (P < .05), and alleviated pathological conditions in NAFLD rats. Based on potential biomarker analysis, RA affected metabolic pathways such as fatty acids biosynthesis, bile acids biosynthesis, and pentose phosphate pathway, delaying the progression of NAFLD. CONCLUSION: RA improved blood lipid levels, liver function, and pathological conditions of NAFLD rats. Meanwhile, affected the metabolic pathways and regulated the synthesis of fatty acids and bile acids in NAFLD rats.

Prepared Radix Polygoni Multiflori and emodin alleviate lipid droplet accumulation in nonalcoholic fatty liver disease through MAPK signaling pathway inhibition.

As one of the most common liver diseases, nonalcoholic fatty liver disease (NAFLD) affects almost one-quarter of the world's population. Although the prevalence of NAFLD is continuously rising, effective medical treatments are still inadequate. Radix Polygoni Multiflori (RPM) is a traditional Chinese herbal medicine. As a processed product of RPM, prepared Radix Polygoni Multiflori (PRPM) has been reported to have antioxidant and anti-inflammatory effects. This study investigated whether PRPM treatment could significantly improve NAFLD. We used recent literature, the Herb database and the SwissADME database to isolate the active compounds of PRPM. The OMIM, DisGeNET and GeneCards databases were used to isolate NAFLD-related target genes, and GO functional enrichment and KEGG pathway enrichment analyses were conducted. Moreover, PRPM treatment in NAFLD model mice was evaluated. The results indicate that the target genes are mainly enriched in the AMPK and de novo lipogenesis signaling pathways and that PRPM treatment improves NAFLD disease in model mice. Here, we found the potential benefits of PRPM against NAFLD and demonstrated in vivo and in vitro that PRPM and its ingredient emodin downregulate phosphorylated P38/P38, phosphorylated ERK1/2 and genes related to de novo adipogenesis signaling pathways and reduce lipid droplet accumulation. In conclusion, our findings revealed a novel therapeutic role for PRPM in the treatment of NAFLD and metabolic inflammation.

Hesperidin Protects Against High-Fat Diet-Induced Lipotoxicity in Rats by Inhibiting Pyroptosis.

It is currently thought that excess fatty acid-induced lipotoxicity in hepatocytes is a critical initiator in the development of nonalcoholic fatty liver disease (NAFLD). Lipotoxicity can induce hepatocyte death; thus, reducing lipotoxicity is one of the most effective therapeutic methods to combat NAFLD. Abundant evidence has shown that hesperidin (HSP), a type of flavanone mainly found in citrus fruits, is able to ameliorate NAFLD, but the molecular mechanisms are unclear. We previously reported that pyroptosis contributed to NAFLD development and that inhibiting pyroptosis contributed to blunting the progression of NAFLD in rat models. Therefore, we questioned whether HSP could contribute to ameliorating NAFLD by modulating pyroptosis. In this study, a high-fat diet (HFD) induced dyslipidemia and hepatic lipotoxicity in rats, and HSP supplementation ameliorated dyslipidemia and insulin resistance. In addition, the HFD also caused pyroptosis in the liver and pancreas, while HSP supplementation ameliorated pyroptosis. In vitro, we found that HSP ameliorated palmitic acid-induced lipotoxicity and pyroptosis in HepG2 and INS-1E cells. In conclusion, we showed for the first time that HSP has a protective effect against liver and pancreas damage in terms of pyroptosis and provides a novel mechanism for the protective effects of HSP on NAFLD.

Non-Pharmacological Approach to Diet and Exercise in Metabolic-Associated Fatty Liver Disease: Bridging the Gap between Research and Clinical Practice.

This review provides a practical and comprehensive overview of non-pharmacological interventions for metabolic-associated fatty liver disease (MASLD), focusing on dietary and exercise strategies. It highlights the effectiveness of coffee consumption, intermittent fasting, and Mediterranean and ketogenic diets in improving metabolic and liver health. The review emphasizes the importance of combining aerobic and resistance training as a critical approach to reducing liver fat and increasing insulin sensitivity. Additionally, it discusses the synergy between diet and exercise in enhancing liver parameters and the role of gut microbiota in MASLD. The paper underscores the need for a holistic, individualized approach, integrating diet, exercise, gut health, and patient motivation. It also highlights the long-term benefits and minimal risks of lifestyle interventions compared to the side effects of pharmacological and surgical options. The review calls for personalized treatment strategies, continuous patient education, and further research to optimize therapeutic outcomes in MASLD management.

A systematic review and meta-analysis of randomized controlled trials to evaluate plant-based omega-3 polyunsaturated fatty acids in nonalcoholic fatty liver disease patient biomarkers and parameters.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is prevalent in 25-30% of British and European populations, representing a potential global public health crisis. Marine omega-3 (n-3) polyunsaturated fatty acids offer well-evidenced benefits to NAFLD biomarkers; however, the effect of plant-based n-3 has not been evaluated with a systematic review and meta-analysis. OBJECTIVE: The review aimed to systematically evaluate the effect of plant-based n-3 supplementation on NAFLD surrogate biomarkers and parameters. DATA SOURCES: Medline (EBSCO), PubMed, CINAHL (EBSCO), Cochrane Central Register of Controlled Trials, the International Clinical Trials Registry Platform, and Google Scholar databases were searched to identify randomized controlled trials published between January 1970 and March 2022 evaluating the impact of plant-based n-3 interventions on diagnosed NAFLD. The review followed the PRISMA checklist and is PROSPERO registered (CRD42021251980). DATA EXTRACTION: A random-effects model and generic inverse variance methods synthesized quantitative data, followed by a leave-one-out method for sensitivity analysis. We identified 986 articles; after the application of selection criteria, six studies remained with 362 patients with NAFLD. RESULTS: The meta-analysis showed that plant-based n-3 fatty acid supplementation significantly reduced alanine aminotransferase (ALT) (mean difference: 8.04 IU/L; 95% confidence interval: 14.70, 1.38; I2 = 48.61%) and plasma/serum triglycerides (44.51 mg/dL; 95% confidence interval: -76.93, -12.08; I2 = 69.93%), alongside body-composition markers in patients with NAFLD (P < 0.05). CONCLUSION: Plant-based n-3 fatty acid supplementation improves ALT enzyme biomarkers, triglycerides, body mass index, waist circumference, and weight loss when combined with lifestyle interventions to increase physical activity and a calorie-controlled diet. Further research is needed to identify the most effective plant-based n-3 sources in larger numbers of patients with NAFLD over longer study durations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021251980.

Late-onset Wilson Disease in a Patient Followed-up for Nonalcoholic Fatty Liver Disease.

A 73-year-old woman was referred to our hospital for persistent liver dysfunction. When the patient was 45 years old, her youngest sister had been diagnosed with Wilson disease (WD). The patient therefore underwent several family screening tests, all of which were unremarkable. She had an annual medical checkup and was diagnosed with liver dysfunction and fatty liver at 68 years old. A liver biopsy and genetic testing were performed, and she was diagnosed with WD; chelation therapy was then initiated. In patients with hepatic disorders and a family history of WD, multiple medical examinations should be conducted, as the development of WD is possible regardless of age.

Noninvasive Diagnostic Technique for Nonalcoholic Fatty Liver Disease Based on Features of Tongue Images.

OBJECTIVE: To investigate a new noninvasive diagnostic model for nonalcoholic fatty liver disease (NAFLD) based on features of tongue images. METHODS: Healthy controls and volunteers confirmed to have NAFLD by liver ultrasound were recruited from China-Japan Friendship Hospital between September 2018 and May 2019, then the anthropometric indexes and sampled tongue images were measured. The tongue images were labeled by features, based on a brief protocol, without knowing any other clinical data, after a series of corrections and data cleaning. The algorithm was trained on images using labels and several anthropometric indexes for inputs, utilizing machine learning technology. Finally, a logistic regression algorithm and a decision tree model were constructed as 2 diagnostic models for NAFLD. RESULTS: A total of 720 subjects were enrolled in this study, including 432 patients with NAFLD and 288 healthy volunteers. Of them, 482 were randomly allocated into the training set and 238 into the validation set. The diagnostic model based on logistic regression exhibited excellent performance: in validation set, it achieved an accuracy of 86.98%, sensitivity of 91.43%, and specificity of 80.61%; with an area under the curve (AUC) of 0.93 [95% confidence interval (CI) 0.68-0.98]. The decision tree model achieved an accuracy of 81.09%, sensitivity of 91.43%, and specificity of 66.33%; with an AUC of 0.89 (95% CI 0.66-0.92) in validation set. CONCLUSIONS: The features of tongue images were associated with NAFLD. Both the 2 diagnostic models, which would be convenient, noninvasive, lightweight, rapid, and inexpensive technical references for early screening, can accurately distinguish NAFLD and are worth further study.

The Effects of Ginger (Zingiber Officinale Roscoe) on Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blinded Placebo-Controlled Clinical Trial.

Nonalcoholic fatty liver disease (NAFLD) is a prominent etiological factor for liver cirrhosis worldwide. It is frequently associated with obesity, diabetes, dyslipidemia, and hypertension. The objective of this study is to assess the efficacy and safety of ginger (Zingiber officinale Roscoe) supplementation in patients with type 2 diabetes mellitus (T2DM) who have NAFLD. In a two-arm, double-blind, placebo-controlled clinical trial, seventy-six patients diagnosed with both T2DM and NAFLD were randomly assigned to receive either ginger powder capsules (1000 mg, twice daily) or placebo capsules (administered in the same manner) for a period of three months. Anthropometric measurements, blood pressure readings, biochemical profiles, and imaging parameters were assessed before and after the intervention. Safety measures were also evaluated. In both the ginger and placebo groups, there was a significant reduction in mean body mass index (BMI), waist and hip circumferences, as well as liver transaminase levels. Moreover, significant improvements in mean systolic and diastolic blood pressures were observed in the ginger group (p = 0.02 and < 0.0001, respectively). Within the ginger group, there was a decrease in serum insulin levels and insulin resistance (HOMA-IR) (p = 0.002 and 0.004, respectively). Furthermore, the ginger group exhibited an improvement in serum HDL-cholesterol level (p = 0.01). However, there were no significant changes in the assessed inflammatory markers or the indices obtained from fibroscan imaging, including steatosis percent and controlled attenuation parameter. This study demonstrates that ginger supplementation can significantly improve mean systolic and diastolic blood pressures. However, it does not have a significant impact on inflammatory markers or fibroscan imaging indices. Nonetheless, the three-month use of ginger improves serum insulin level, insulin resistance (HOMA-IR), and HDL-cholesterol level compared to baseline values. Further investigations with longer durations and larger sample sizes are recommended.

Preventive mechanisms of Chinese Tibetan medicine Triphala against nonalcoholic fatty liver disease.

BACKGROUND: Triphala (TLP), as a Chinese Tibetan medicine composing of Emblica officinalis, Terminalia chebula and Terminalia bellirica (1.2:1.5:1), exhibited hepatoprotective, hypolipidemic and gut microbiota modulatory effects. Nonetheless, its roles in prevention of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) and the related mechanistic insights involving the interplay of gut microbiota and hepatic inflammation are not known. PURPOSE: The present study seeks to determine if TLP would prevent HFD-induced NAFLD in vivo and its underlying mechanisms from the perspectives of gut microbiota, metabolites, and hepatic inflammation. METHODS: TLP was subjected to extraction and chemo-profiling, and in vivo evaluation in HFD-fed rats on hepatic lipid and inflammation, intestinal microbiota, short-chain fatty acids (SCFAs) and permeability, and body weight and fat content profiles. RESULTS: The TLP was primarily constituted of gallic acid, corilagin and chebulagic acid. Orally administered HFD-fed rats with TLP were characterized by the growth of Ligilactobacillus and Akkermansia, and SCFAs (acetic/propionic/butyric acid) secretion which led to increased claudin-1 and zonula occludens-1 expression that reduced the mucosal permeability to migration of lipopolysaccharides (LPS) into blood and liver. Coupling with hepatic cholesterol and triglyceride lowering actions, the TLP mitigated both inflammatory (ALT, AST, IL-1ß, IL-6 and TNF-α) and pro-inflammatory (TLR4, MYD88 and NF-κB P65) activities of liver, and sequel to histopathological development of NAFLD in a dose-dependent fashion. CONCLUSION: TLP is promisingly an effective therapy to prevent NAFLD through modulating gut microbiota, mucosal permeability and SCFAs secretion with liver fat and inflammatory responses.

Erchen decoction alleviates the progression of NAFLD by inhibiting lipid accumulation and iron overload through Caveolin-1 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: A combination of 6 different Chinese herbs known as Erchen decoction (ECD) has been traditionally used to treat digestive tract diseases and found to have a protective effect against nonalcoholic fatty liver disease (NAFLD). Despite its efficacy in treating NAFLD, the precise molecular mechanism by which Erchen Decoction regulated iron ion metabolism to prevent disease progression remained poorly understood. AIM OF STUDY: Our study attempted to confirm the specific mechanism of ECD in reducing lipid and iron in NAFLD from the perspective of regulating the expression of Caveolin-1 (Cav-1). STUDY DESIGN: In our study, the protective effect of ECD was investigated in Palmitic Acid + Oleic Acid-induced hepatocyte NAFLD model and high-fat diet-induced mice NAFLD model. To investigate the impact of Erchen Decoction (ECD) on lipid metabolism and iron metabolism via mediating Cav-1 in vitro, Cav-1 knockdown cell lines were established using lentivirus-mediated transfection techniques. MATERIALS AND METHODS: We constructed NAFLD model by feeding with high-fat diet for 12 weeks in vivo and Palmitic Acid + Oleic Acid treatment for 24 h in vitro. The regulation of Lipid and iron metabolism results by ECD were detected by serological diagnosis, immunofluorescent and immunohistochemical staining, and western blotting. The binding ability of 6 small molecules of ECD to Cav-1 was analyzed by molecular docking. RESULTS: We demonstrated that ECD alleviated the progression of NAFLD by inhibiting lipid accumulation, nitrogen oxygen stress, and iron accumulation in vivo and in vitro experiments. Furthermore, ECD inhibited lipid and iron accumulation in liver by up-regulating the expression of Cav-1, which indicated that Cav-1 was an important target for ECD to exert its curative effect. CONCLUSIONS: In summary, our study demonstrated that ECD alleviated the accumulation of lipid and iron in NAFLD through promoting the expression of Cav-1, and ECD might serve as a novel Cav-1 agonist to treat NAFLD.

n-3 polyunsaturated fatty acids in phospholipid or triacylglycerol form attenuate nonalcoholic fatty liver disease via mediating cannabinoid receptor 1/adiponectin/ceramide pathway.

n-3 polyunsaturated fatty acids (PUFA) have shown to exert beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Supplements of n-3 PUFA occur in either phospholipid or triacylglycerol form. The present study aimed to compare whether the different n-3 PUFA of marine-origin, namely krill oil, DHA/EPA-phospholipid (PL), and EPA/DHA-triacylglycerol (TAG) forms had differential abilities to ameliorate NAFLD. The NAFLD model was established in mice fed a high-fat and high-cholesterol diet (HFD). The mice showed evidence of weight gain, dyslipidemia, insulin resistance and hepatic steatosis after 9 weeks of HFD, while the three forms of the n-3 PUFA reduced hepatic TAG accumulation, fatty liver and improved insulin instance, and hepatic biomarkers after 9 weeks of intervention. Of these, krill oil intervention significantly reduced adipocyte hypertrophy and hepatic steatosis in comparison with DHA/EPA-PL and EPA/DHA-TAG groups. Importantly, only krill oil intervention significantly reduced serum alanine transaminase, aspartate transaminase concentrations and low-density lipoprotein-cholesterol, compared with the HFD group. Supplemental n-3 PUFA lowered circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations, compared with the HFD group, which was associated with down-regulating CB1 and upregulating adiponectin expressions in adipose tissue. Besides, targeted lipidomic analyses indicated that the increased adiponectin levels were accompanied by reductions in hepatic ceramide levels. The reduced ceramide levels were associated with inhibiting lipid synthesis and increasing fatty acid ß-oxidation, finally inhibiting TAG accumulation in the liver. Through mediating CB1/adiponectin/ceramide pathway, the present study suggested that administration of krill oil had superior health effects in the therapy of NAFLD in comparison with DHA/EPA-PL and EPA/DHA-TAG.