Effect Of Non-alcoholic Fatty Liver Disease Research Articles

Non-alcoholic fatty liver disease changes the expression and activity of hepatic drug-metabolizing enzymes and transporters in rats

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, which can cause serious complications and gradually increase the mortality rate. However, the effects of NAFLD on drug-metabolizing enzymes and transporters remain unclear, which may cause some confusion regarding patient medication. In this study, a NAFLD rat model was constructed by feeding rats with methionine and choline deficiency diets for 6 weeks, and the mRNA and protein levels of drug-metabolizing enzymes and transporter were analyzed by real-time fluorescent quantitative PCR and Western blot, respectively. The activity of drug-metabolizing enzymes was detected by cocktail methods. In the NAFLD rat model, the mRNA expression of phase I enzymes, phase II enzymes, and transporters decreased. At the protein level, only CYP1A1, CYP1B1, CYP2C11, and CYP2J3 presented a decrease. In addition, the activities of CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP3A2, UGT1A1, UGT1A3, UGT1A6, and UGT1A9 decreased. These changes may be caused by the alteration of FXR, HNF4α, LXRα, LXRβ, PXR, and RXR. In conclusion, NAFLD changes the expression and activity of hepatic drug-metabolizing enzymes and transporters in rats, which may affect drug metabolism and pharmacokinetics. In clinical medication, drug monitoring should be strengthened to avoid potential risks.

Non-Alcoholic Fatty Liver Disease May Be a Risk Factor for Liver Metastasis After Radical Surgery for Colorectal Cancer: A Retrospective Study.

Distant metastasis develops in approximately one-third of patients with colorectal cancer (CRC) who undergo radical surgery, and colorectal liver metastasis (CRLM) is the most common form of distant metastasis in CRC. Hepatectomy is the only potentially curative treatment for CRLM, but few patients with metastatic CRC meet the criteria for this radical resection, and the 5-year survival rate is poor. Identifying risk factors for CRLM is critical. Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for CRC. However, the effect of NAFLD on CRC liver metastasis after radical surgery remains unclear. Therefore, we examined the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC. We retrospectively analyzed data from 388 patients who underwent curative surgery for CRC at our hospital between April 2008 and March 2015. The patients' clinical results, surgical procedures, postoperative course, and pathological and survival data were collected from the hospital records. The NAFLD fibrosis score was calculated and used to divide the patients into two groups (NAFLD and non-NAFLD). Recurrence was observed in 83/388 (21.4%) patients after a mean follow-up of 65.6 ± 15.1months. Twenty-five patients had liver metastasis: 8 in the NAFLD group (8/45; 17.8%) and 17 in the non-NALFD group (17/343; 5.0%) (p = 0.004). Liver metastasis-free survival was significantly worse in the NAFLD than non-NAFLD group (p < 0.001). NAFLD and cancer stage were independent risk factors for liver metastasis recurrence. NAFLD may be a risk factor for liver metastasis in patients with CRC who undergo curative surgery.

Nonalcoholic fatty liver disease: Current therapies and future perspectives in drug delivery

Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.

The Effect of Non-Alcoholic Fatty Liver Disease on Weight Loss and Resolution of Obesity-Related Disorders After Bariatric Surgery

BackgroundPatients undergoing bariatric surgery have a high incidence of non-alcoholic fatty liver disease (NAFLD). However, the effect of NAFLD or non-alcoholic steatohepatitis (NASH) on the weight loss and resolution of obesity-related disorders is a matter of debate.MethodsIn this study, we compare the long-term outcomes after bariatric with the presence of NAFLD in the liver biopsy at the time of surgery.ResultsThe follow-up was available for 226 out of 288 patients. The mean follow-up time was 24.9 (± 13.6) months. The baseline histology showed that 112 patients (38.9%) had no NASH, 70 (24.3%) were borderline, and 106 (36.8%) had NASH. At follow-up, the mean BMI dropped from (52 ± 10.2) to (36.6 ± 8) kg/m 2. Excess weight loss (EWL) was similar in all NAFLD groups. Type 2 diabetes mellitus dropped from 35.7 to 11.4%, hypertension from 65.6 to 36.7%, hyperlipidemia from 62.3 to 33%, and obstructive sleep apnea from 37.5 to 14.9%. Only hyperlipidemia was significantly associated with NASH compared to the groups with no NASH or borderline NASH (p value = 0.002 and p value = 0.04, respectively) during the first two years of follow-up.ConclusionThe beneficial effects of bariatric surgery are evident across all patients with NAFLD. Patients with NASH have comparable outcomes regarding weight loss and resolution of obesity-related comorbidities.

Lonicerae flos polysaccharides improve nonalcoholic fatty liver disease by activating the adenosine 5'-monophosphate-activated protein kinase pathway and reshaping gut microbiota.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver cirrhosis and cancer. Lonicerae flos polysaccharides (LPs) have been shown to be effective in treating metabolic diseases; however, the therapeutic effects and underlying molecular mechanisms of LPs in NAFLD remain unclear. The objective of this study was to investigate the morphological characterization of Lonicerae flos polysaccharides (LPs) and the mechanism of LPs in relieving NAFLD. The morphology of LPs was observed using atomic force microscopy (AFM), X-ray diffraction (XRD), thermal weight (TG), and thermal weight derivative (DTG); NAFLD mice were treated with LPs at the same time as they were induced with a Western diet, and then the indexes related to glycolipid metabolism, fibrosis, inflammation, and autophagy in the serum and liver of the mice were detected. The atomic force microscope analysis results indicated that the LPs displayed sugar-chain aggregates, exhibited an amorphous structure, and were relatively stable in thermal cracking at 150 °C. It was also found that LPs exerted therapeutic effects in NAFLD. The LPs prevented high-fat and -cholesterol diet-induced NAFLD progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, fibrosis, and autophagy. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor compound C abrogated LP-induced hepatoprotection in mice with NAFLD. The LPs further treated NAFLD by reshaping the structure of the gut microbiota, in which Desulfovibrio bacteria plays a key roles. Lonicerae flos polysaccharides exert protective effects against NAFLD in mice by improving the structure of the intestinal flora and activating the AMPK signaling pathway. © 2023 Society of Chemical Industry.

Sodium-glucose cotransporter-2 inhibitors improve FibroScan-aspartate aminotransferase scores in patients with nonalcoholic fatty liver disease complicated by type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by excessive lipid accumulation in the liver, and its global incidence is increasing. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are oral antidiabetes drugs that promote glucose excretion into the urine and have been reported to exert therapeutic effects in NAFLD, but liver stiffness measurements (LSMs) determined by transient elastography are inconsistent. In addition, the effects of SGLT2is on the FibroScan-aspartate aminotransferase (FAST) scores have not been reported. We evaluated the effect of SGLT2is on patients with NAFLD complicated by type 2 diabetes using biochemical tests, transient elastography, and FAST scores. Fifty-two patients with type 2 diabetes complicated by NAFLD who started SGLT2i treatment between 2014 and 2020 at our hospital were selected from the database. Pre- and post-treatment serum parameters, transient elastography, and FAST scores were compared. After 48 weeks of SGLT2i treatment, body weight, fasting blood glucose, hemoglobin A1c, AST, alanine aminotransferase, gamma-glutamyltransferase, uric acid, fibrosis-4 index, and AST to platelet ratio index improved. Median LSM decreased from 7.0 kPa to 6.2 kPa ( P = 0.023) and the median controlled attenuation parameter decreased from 304 dB/m to 283 dB/m ( P = 0.022). Median FAST score decreased from 0.40 to 0.22 ( P < 0.001), and the number of cases with a cutoff value of ≥0.35 decreased from 15 to 6 ( P = 0.001). SGLT2i use not only improves weight loss and blood glucose levels but also improves hepatic fibrosis by ameliorating hepatic steatosis and inflammation.

0869 Non-Alcoholic Fatty Liver Disease is Associated with Worse Outcomes in Atrial Fibrillation patients with Obstructive Sleep Apnea

Abstract Introduction Managing atrial fibrillation (AF) in patients with obstructive sleep apnea (OSA) is challenging and often associated with worse outcomes. Non-alcoholic fatty liver disease (NAFLD) is shown to be associated with increased cardiovascular morbidity and mortality. The effect of NAFLD on AF in patients with OSA is not well studied. This study aims to investigate this association in hospitalized patients. Methods We queried the National Inpatient Sample (NIS) between 2017-2020 for adult patients hospitalized for AF with history of OSA &amp; had NAFLD. The primary outcome was in-hospital mortality. The secondary outcomes were cardiogenic shock, gastrointestinal bleeding (GIB), cardiac arrest, invasive mechanical ventilation (IMV) and length of stay (LOS). Multivariable logistic and Poisson regression analyses were used to estimate clinical outcomes. Outcomes were adjusted for age, gender, race, heart failure, diabetes, CKD, chronic respiratory failure, stroke and history of MI. P-value &amp;lt; 0.05 was statistically significant. Results We identified 1,843,865 hospitalizations for AF with history of OSA: NAFLD in 61,235 (3.4%). AF with OSA and NAFLD vs. no NAFLD had mean age 68.4 vs. 70.6, males 65.2% vs. 64.1%, white 78.2% vs. 80.2%, black 9.3% vs. 10.2%, obesity 45.7% vs. 46.5%, heart failure 69.2% vs. 59.6%, diabetes 59.2% vs. 51.1%, anemia 23.5% vs. 17.2%, CKD 52.4% vs. 40% and COPD 38.2% vs. 39.1%. In-hospital mortality was 11.4% in the NAFLD group vs. 2.5% in the non-NAFLD group (aOR 5.2, P&amp;lt; 0.001). NAFLD vs. non-NAFLD groups had GIB 9.4% vs. 4.5% (aOR 2.1, P&amp;lt; 0.001), cardiac arrest 3.4% vs. 0.9% (aOR 3.4, P&amp;lt; 0.001), cardiogenic shock 7% vs. 1.2% (aOR 4.9, P&amp;lt; 0.001), IMV 10.9% vs. 3.4% (aOR 3.3, P&amp;lt; 0.001) and LOS 7.7 vs. 5.6 (aIRR 1.27, P&amp;lt; 0.001). Conclusion Our study shows that NAFLD has worsened the outcomes of patients admitted with AF and has history of OSA. The fivefold increase in in-hospital mortality is likely related to the increase in in-hospital hemorrhagic events and cardiac arrest. Clinicians should be aware of this association. Further research is needed to mitigate the detrimental effect of liver disease on OSA and AF patients. Support (if any)

Hepatic Steatosis but Not Fibrosis Is Independently Associated with Poor Outcomes in Patients with Inflammatory Bowel Disease.

Increased prevalence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) has been reported. However, the effects of NAFLD on the outcome of IBD remains unclear. We investigated whether the presence of NAFLD could influence the outcomes of patients with IBD. We recruited 3,356 eligible patients with IBD into our study between November 2005 and November 2020. Hepatic steatosis and fibrosis were diagnosed using hepatic steatosis index of ≥30 and fibrosis-4 of ≥1.45, respectively. The primary outcome was clinical relapse, defined based on the following: IBD-related admission, surgery, or first use of corticosteroids, immunomodulators, or biologic agents for IBD. The prevalence of NAFLD in patients with IBD was 16.7%. Patients with hepatic steatosis and advanced fibrosis were older, had a higher body mass index, and were more likely to have diabetes (all p<0.05). Hepatic steatosis was independently associated with increased risks of clinical relapse in patients with ulcerative colitis and Crohn's disease, whereas fibrotic burden in the liver was not. Future studies should investigate whether assessment and therapeutic intervention for NAFLD will improve the clinical outcomes of patients with IBD.

Gut metabolomics and 16S rRNA sequencing analysis of the effects of arecoline on non-alcoholic fatty liver disease in rats.

Introduction: Non-alcoholic fatty liver disease (NAFLD) has gradually become the primary cause of fatty liver disease. Betel nuts have been used to treat gastrointestinal diseases. Methods: In the present study, we analyzed the pathology, serology, gut flora, and metabolites in a rat model of NAFLD, with and without betel nut alkaloid treatment, using an integrated approach involving pathology, serological testing, 16S rRNA gene sequencing, and ultra-performance liquid chromatography-mass spectrometry metabolomics. Results: Two rats were used for model validation. Thirty SD rats were included and divided into the normal group (C group), NAFLD model group (M group), low-dose group, medium-dose group (T group), and high-dose group with intraperitoneal injection of arecoline. The expression of blood lipids was significantly downregulated at all three arecoline concentrations (p < 0.05). Alpha-diversity analysis of the intestinal flora showed significant differences among the three groups, with a significant reduction in population diversity in the M group and a recovery of population diversity after arecoline treatment. At the phylum level, the relative abundance of Firmicutes was significantly higher in the T group and Proteobacteria in the M group. The KEGG metabolic pathways included polyketide sugar unit biosynthesis and hypertrophic cardiomyopathy. Thirty-three significantly different metabolites were identified among the groups. Significantly different metabolites between groups T and M included indolepyruvate, 2-deoxystreptamine, sakuranetin, glycyl-leucine, and riboflavin. The KEGG metabolic pathway suggested a potential role for arachidonic acid metabolism, serotonergic synapses, neuroactive ligand-receptor interactions, tyrosine metabolism, and regiomelanin. Vitamin digestion and absorption, as well as regulation of lipolysis in adipocytes, were the main metabolic pathways that distinguished the T vs. M groups. PGE2 is involved in several metabolic pathways. Correlation analysis showed that 29 bacterial species were significantly associated with PGE2 levels in the M and T groups. Vagococcus, Lawsonia, Christensenella, unidentified Erysipelotrichaceae, unidentified Coriobacteriaceae, and five other bacterial groups are unique in the PGE2 metabolic pathway regulated by arecoline. Discussion: Arecoline has lipid-lowering effects and may exert therapeutic effects in NAFLD through intestinal metabolites and intestinal flora, as well as through the Butyricicoccus/Christensenella/Coriobacteriaceae-COX2/PGE2 pathway. Thus, arecoline may represent a potential drug or target for NAFLD treatment.

Swietenine Alleviates Nonalcoholic Fatty Liver Disease in Diabetic Mice via Lipogenesis Inhibition and Antioxidant Mechanisms.

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine's effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway.

P200 Hepatic Steatosis but not Fibrosis is independently associated with poor outcomes in patients with Inflammatory Bowel Disease

Abstract Background Increased prevalence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) has been reported; however, the effects of NAFLD on the outcome of IBD remains unclear. We investigated whether the presence of NAFLD could influence the outcomes of patients with IBD. Methods We recruited 3,356 eligible patients with IBD into our study between November 2005 and November 2020. Hepatic steatosis and fibrosis were diagnosed using hepatic steatosis index (HSI) of ≥30 and fibrosis-4 (FIB-4) of ≥1.45, respectively. Primary outcome was clinical relapse, defined based on the following: IBD-related admission, surgery, or first use of corticosteroids, immunomodulators, or biologics agents for IBD. Results Prevalence of NAFLD in patients with IBD was 16.7%. Patients with hepatic steatosis and advanced fibrosis were older, had a higher body mass index, and were more likely to have diabetes (all p&amp;lt;0.05). Multivariate cox regression analysis revealed that hepatic steatosis was independently associated with an increased risk of relapse in patients with ulcerative colitis (UC) (hazard ratio [HR] 1.697, 95% confidence interval [CI] 1.291-2.230; p&amp;lt;0.001) and Crohn’s disease (CD) (HR 1.536, 95% CI 1.130-2.087; p=0.006). Advanced liver fibrosis was not associated with an increased risk of clinical relapse in patients with UC or CD (all p&amp;gt;0.05). Conclusion Hepatic steatosis was independently associated with increased risks of clinical relapse in patients with UC and CD, whereas fibrotic burden in the liver was not. Future studies should investigate whether the assessment and therapeutic intervention of NAFLD will improve clinical outcomes of patients with IBD.

Pioglitazone, Bladder Cancer, and the Presumption of Innocence

Thiazolidinediones are potent exogenous agonists of PPAR-γ that augment the effects of insulin to its cellular targets, mainly at the level of adipose tissue. Pioglitazone, the main thiazolidinedione in clinical practice, has shown cardiovascular and renal benefits in patients with type 2 diabetes, durable reduction of glycated hemoglobulin levels, important improvements of several components of the metabolic syndrome, and beneficial effects of non-alcoholic fatty liver disease. Despite all of its established advantages, the controversy for an increased risk of developing bladder cancer, combined with the advent of newer drug classes that achieved major cardiorenal effects, have significantly limited its use spreading a persistent shadow of doubt for its future role. Pubmed, Google, and Scope databases have been thoroughly searched, and relevant studies were selected. This paper thoroughly explores both in vitro and in vivo (animal models and humans) studies that investigated the possible association of pioglitazone with bladder cancer. Currently, the association of pioglitazone with bladder cancer cannot be based on solid evidence. This evidence cannot justify its low clinical administration, especially in the present era of individualised treatment strategies. Definite clarification of this issue is imperative and urgently anticipated from future high quality and rigorous pharmacoepidemiologic research, keeping in mind its unique mechanism of action and its significant pleiotropic effects.

Critical Overview of Hepatic Factors That Link Non-Alcoholic Fatty Liver Disease and Acute Kidney Injury: Physiology and Therapeutic Implications.

Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases.

The Efficacy of Oligonol in Nonalcoholic Fatty Liver Disease: A Randomized Double-Blinded Placebo-Controlled Trial

Introduction: Oligonol, an oligomerized-polyphenol from Litchi chinensis extract, has been shown to alleviate metabolic syndrome. The aim of this study was to evaluate the effects of oligonol in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Adult patients with NAFLD defined by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) ≥11% were enrolled and then randomly assigned to receive either oligonol or placebo capsules. Primary endpoint was ≥30% reduction in MRI-PDFF at 24 weeks. Secondary outcomes were reductions in bodyweight, waist circumference, alanine transaminase, fasting blood sugar, and lipid profiles at week 24. Results: Forty patients were enrolled (n = 20/group). Primary endpoint was achieved in 20% in the oligonol group and 15% in the placebo group (p = 0.50). The authors found a reduction in MRI-PDFF between weeks 0 and 24 in the oligonol group; however, the change was not different from the placebo group. Secondary outcomes were similar between two groups. Discussion: Oligonol has not shown a significant therapeutic effect in NAFLD. Future studies with a longer duration of therapy might be needed to achieve the primary endpoint. Clinical Trial Registration Number: Thai Clinical Trial Registry identification number: TCTR20200814001.

Association between non-alcoholic fatty liver disease and metabolically healthy deterioration across different body shape phenotypes at baseline and change patterns

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome (MetS), and the relationship between NAFLD and metabolic deterioration remains unclear. This study aimed to investigate dynamic changes in metabolically healthy phenotypes and to assess the impact of non-alcoholic fatty liver disease (NAFLD) on the conversion from metabolically healthy (MH) to metabolically unhealthy (MU) phenotypes across body shape phenotypes and phenotypic change patterns. We defined body shape phenotypes using both the body mass index (BMI) and waist circumference (WC) and defined metabolic health as individuals scoring ≤ 1 on the NCEP-ATP III criteria, excluding WC. A total of 12,910 Chinese participants who were MH at baseline were enrolled in 2013 and followed-up in 2019 or 2020. During a median follow-up of 6.9 years, 27.0% (n = 3,486) of the MH individuals developed an MU phenotype. According to the multivariate Cox analyses, NAFLD was a significant predictor of conversion from the MH to MU phenotype, independent of potential confounders (HR: 1.12; 95% confidence interval: 1.02–1.22). For the MH-normal weight group, the relative risk of NAFLD in phenotypic conversion was 1.21 (95% CI 1.03–1.41, P = 0.017), which was relatively higher than that of MH-overweight/obesity group (HR: 1.14, 95% CI 1.02–1.26, P = 0.013). Interestingly, the effect of NAFLD at baseline on MH deterioration was stronger in the “lean” phenotype group than in the “non-lean” phenotype group at baseline and in the “fluctuating non-lean” phenotype change pattern group than in the “stable non-lean” phenotype change pattern group during follow-up. In conclusion, lean NAFLD is not as benign as currently considered and requires more attention during metabolic status screening.

Exploration of Shared Gene Signatures and Molecular Mechanisms Between Periodontitis and Nonalcoholic Fatty Liver Disease.

Background: Periodontitis is associated with periodontal tissue damage and teeth loss. Nonalcoholic fatty liver disease (NAFLD) has an intimate relationship with periodontitis. Nevertheless, interacted mechanisms between them have not been clear. This study was intended for the exploration of shared gene signatures and latent therapeutic targets in periodontitis and NAFLD. Methods: Microarray datasets of periodontitis and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. The weighted gene co-expression network analysis (WGCNA) was utilized for the acquisition of modules bound up with NAFLD and periodontitis. We used ClueGO to carry out biological analysis on shared genes to search their latent effects in NAFLD and periodontitis. Another cohort composed of differential gene analysis verified the results. The common microRNAs (miRNAs) in NAFLD and periodontitis were acquired in the light of the Human microRNA Disease Database (HMDD). According to miRTarbase, miRDB, and Targetscan databases, latent target genes of miRNAs were forecasted. Finally, the miRNAs–mRNAs network was designed. Results: Significant modules with periodontitis and NAFLD were obtained via WGCNA. GO enrichment analysis with GlueGo indicated that damaged migration of dendritic cells (DCs) might be a common pathophysiologic feature of NAFLD and periodontitis. In addition, we revealed common genes in NAFLD and periodontitis, including IGK, IGLJ3, IGHM, MME, SELL, ENPP2, VCAN, LCP1, IGHD, FCGR2C, ALOX5AP, IGJ, MMP9, FABP4, IL32, HBB, FMO1, ALPK2, PLA2G7, MNDA, HLA-DRA, and SLC16A7. The results of differential analysis in another cohort were highly accordant with the findings of WGCNA. We established a comorbidity model to explain the underlying mechanism of NAFLD secondary to periodontitis. Finally, the analysis of miRNA pointed out that hsa-mir-125b-5p, hsa-mir-17-5p, and hsa-mir-21-5p might provide potential therapeutic targets. Conclusion: Our study initially established a comorbidity model to explain the underlying mechanism of NAFLD secondary to periodontitis, found that damaged migration of DCs might be a common pathophysiological feature of NAFLD and periodontitis, and provided potential therapeutic targets.

Silybin regulates P450s activity by attenuating endoplasmic reticulum stress in mouse nonalcoholic fatty liver disease.

Cytochrome P450s are important phase I metabolic enzymes located on endoplasmic reticulum (ER) involved in the metabolism of endogenous and exogenous substances. Our previous study showed that a hepatoprotective agent silybin restored CYP3A expression in mouse nonalcoholic fatty liver disease (NAFLD). In this study we investigated how silybin regulated P450s activity during NAFLD. C57BL/6 mice werefed a high-fat-diet (HFD) for 8 weeks to induce NAFLD, and were administered silybin (50, 100 mg ·kg-1 ·d-1, i.g.) in the last 4 weeks. We showed that HFD intake induced hepatic steatosis and ER stress, leading to significant inhibition on the activity of five primary P450s including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A in liver microsomes. These changes were dose-dependently reversed by silybin administration. The beneficial effects of silybin were also observed in TG-stimulated HepG2 cells in vitro. To clarify the underlying mechanism, we examined the components involved in the P450 catalytic system, membrane phospholipids and ER membrane fluidity, and found that cytochrome b5 (cyt b5) was significantly downregulated during ER stress, and ER membrane fluidity was also reduced evidenced by DPH polarization and lower polyunsaturated phospholipids levels. The increased ratios of NADP+/NADPH and PC/PE implied Ca2+ release and disruption of cellular Ca2+ homeostasis resulted from mitochondria dysfunction and cytochrome c (cyt c) release. The interaction between cyt c and cyt b5 under ER stress was an important reason for P450s activity inhibition. The effect of silybin throughout the whole course suggested that it regulated P450s activity through its anti-ERstress effect in NAFLD. Our results suggest that ER stress may be crucial for the inhibition of P450s activity in mouse NAFLD and silybin regulates P450s activity by attenuating ER stress.

Mendelian Randomization Rules Out Causation Between Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease.

Background: Inflammatory bowel disease (IBD) and non-alcoholic fatty liver disease (NAFLD) usually co-exist clinically. However, whether such association is causal is still unknown. Methods: Genetic variants were extracted as instrumental variables from the largest genome-wide association study (GWAS) of IBD, Crohn’s disease (CD) and ulcerative colitis (UC) with 25,042 cases and 34,915 controls (GWAS p-value < 5 × 10−8). Information of genetic variants in NAFLD was extracted from a GWAS with 1,483 cases and 17,781controls. Also, liver fat content (LFC) was included as the outcome. Then, a bi-direction Mendelian randomization (MR) was carried out to appraise the causal relationship between NAFLD on IBD. Besides, a multivariable MR (MVMR) design was carried to adjust for body mass index (BMI) and type 2 diabetes (T2D) as well. Results: Generally, IBD might not affect the risk of NAFLD (OR = 0.994 [0.970, 1.019]), together with its subtypes including UC and CD. However, genetically-elevated risk of IBD might cause liver fat accumulation (beta = 0.019, p-value = 0.016) while turning insignificant at Bonferroni correction. Besides, no causal effect of NAFLD on IBD was observed (OR = 0.968 [0.928, 1.009]), together with UC and CD. Also, genetically-elevated LFC could not impact IBD, UC and CD either. The MR CAUSE analysis supported these null associations and MVMR analysis also supported such null associations even after adjusting for BMI and T2D. Conclusion: This MR study ruled out the causal relationship between IBD and NAFLD, suggesting therapeutics targeting NAFLD might not work for IBD and vice versa.

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model.

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

Hepatoprotective Effects of Ixeris chinensis on Nonalcoholic Fatty Liver Disease Induced by High-Fat Diet in Mice: An Integrated Gut Microbiota and Metabolomic Analysis.

Ixeris chinensis (Thunb.) Nakai (IC) is a folk medicinal herb used in Mongolian medical clinics for the treatment of hepatitis and fatty liver diseases even though its pharmacological mechanism has not been well characterized. This study investigated the hepatoprotective mechanism of IC on mice with nonalcoholic fatty liver disease (NAFLD) by integrating gut microbiota and metabolomic analysis. A high-fat diet (HFD) was used to develop nonalcoholic fatty liver disease, after which the mice were treated with oral IC (0.5, 1.5 and 3.0 g/kg) for 10 weeks. HFD induced NAFLD and the therapeutic effects were characterized by pathological and histological evaluations, and the serum indicators were analyzed by ELISA. The gut microbial and metabolite profiles were studied by 16S rRNA sequencing and untargeted metabolomic analysis, respectively. The results showed that the administration of IC resulted in significant decreases in body weight; liver index; serum biomarkers such as ALT, TG, and LDL-C; and the liver inflammatory factors IL-1β, IL-6, and TNF-α. The 16S rRNA sequencing results showed that administration of IC extract altered both the composition and abundance of the gut microbiota. Untargeted metabolomic analysis of liver samples detected a total of 212 metabolites, of which 128 were differentially expressed between the HFD and IC group. IC was found to significantly alter the levels of metabolites such as L-glutamic acid, pyridoxal, ornithine, L-aspartic acid, D-proline, and N4-acetylaminobutanal, which are involved in the regulation of glutamine and glutamate, Vitamin B6 metabolism, and arginine and proline metabolic pathways. Correlation analysis indicated that the effects of the IC extract on metabolites were associated with alterations in the abundance of Akkermansiaceae, Lachnospiraceae, and Muribaculaceae. Our study revealed that IC has a potential hepatoprotective effect in NAFLD and that its function might be linked to improvements in the composition of gut microbiota and their metabolites.