Non-alcoholic Fatty Liver Disease Phenotype Research Articles

Integrated omics analysis for characterization of the contribution of high fructose corn syrup to non-alcoholic fatty liver disease in obesity

BackgroundHigh-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD. AimBy engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions. MethodsHerein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity. ResultsAlthough HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD. ConclusionOur results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance.

Identification of shared genetic architecture between non-alcoholic fatty liver disease and type 2 diabetes: A genome-wide analysis.

The incidence of complications of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) has been increasing. In order to identify the shared genetic architecture of the two disease phenotypes of NAFLD and T2D, a European population-based GWAS summary and a cross-trait meta-analysis was used to identify significant shared genes for NAFLD and T2D. The enrichment of shared genes was then determined through the use of functional enrichment analysis to investigate the relationship between genes and phenotypes. Additionally, differential gene expression analysis was performed, significant differentially expressed genes in NAFLD and T2D were identified, genes that overlapped between those that were differentially expressed and cross-trait results were reported, and enrichment analysis was performed on the core genes that had been obtained in this way. Finally, the application of a bidirectional Mendelian randomization (MR) approach determined the causal link between NAFLD and T2D. A total of 115 genes were discovered to be shared between NAFLD and T2D in the GWAS analysis. The enrichment analysis of these genes showed that some were involved in the processes such as the decomposition and metabolism of lipids, phospholipids, and glycerophospholipids. Additionally, through the use of differential gene expression analysis, 15 core genes were confirmed to be linked to both T2D and NAFLD. They were correlated with carcinoma cells and inflammation. Furthermore, the bidirectional MR identified a positive causal relationship between NAFLD and T2D. Our study determined the genetic structure shared between NAFLD and T2D, offering a new reference for the genetic pathogenesis and mechanism of NAFLD and T2D comorbidities.

Subclinical liver traits are associated with structural and hemodynamic brain imaging markers.

Impaired liver function affects brain health and therefore understanding potential mechanisms for subclinical liver disease is essential. We assessed the liver-brain associations using liver measures with brain imaging markers, and cognitive measures in the general population. Within the population-based Rotterdam Study, liver serum and imaging measures (ultrasound and transient elastography), metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD) and fibrosis phenotypes, and brain structure were determined in 3493 non-demented and stroke-free participants in 2009-2014. This resulted in subgroups of n=3493 for MAFLD (mean age 69 ± 9 years, 56% ♀), n=2938 for NAFLD (mean age 70 ± 9 years, 56% ♀) and n=2252 for fibrosis (mean age 65 ± 7 years, 54% ♀). Imaging markers of small vessel disease and neurodegeneration, cerebral blood flow (CBF) and brain perfusion (BP) were acquired from brain MRI (1.5-tesla). General cognitive function was assessed by Mini-Mental State Examination and the g-factor. Multiple linear and logistic regression models were used for liver-brain associations and adjusted for age, sex, intracranial volume, cardiovascular risk factors and alcohol use. Higher gamma-glutamyltransferase (GGT) levels were significantly associated with smaller total brain volume (TBV, standardized mean difference (SMD), -0.02, 95% confidence interval (CI) (-0.03 to -0.01); p=8.4·10-4 ), grey matter volumes, and lower CBF and BP. Liver serum measures were not related to small vessel disease markers, nor to white matter microstructural integrity or general cognition. Participants with ultrasound-based liver steatosis had a higher fractional anisotropy (FA, SMD 0.11, 95% CI (0.04 to 0.17), p=1.5·10-3 ) and lower CBF and BP. MAFLD and NAFLD phenotypes were associated with alterations in white matter microstructural integrity (NAFLD ~ FA, SMD 0.14, 95% CI (0.07 to 0.22), p=1.6·10-4 ; NAFLD ~ mean diffusivity, SMD -0.12, 95% CI (-0.18 to -0.05), p=4.7·10-4 ) and also with lower CBF and BP (MAFLD ~ CBF, SMD -0.13, 95% CI (-0.20 to -0.06), p=3.1·10-4 ; MAFLD ~ BP, SMD -0.12, 95% CI (-0.20 to -0.05), p=1.6·10-3 ). Furthermore, fibrosis phenotypes were related to TBV, grey and white matter volumes. Presence of liver steatosis, fibrosis and elevated serum GGT are associated with structural and hemodynamic brain markers in a population-based cross-sectional setting. Understanding the hepatic role in brain changes can target modifiable factors and prevent brain dysfunction.

Mini review: STING activation during non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases serving as a major threat to human health. While the pathogenesis of NAFLD is multi-factorial, inflammation is considered a critical factor driving the development and progression of NAFLD phenotype, including liver fibrosis. As an essential mediator of innate immunity, stimulator of interferon genes (STING) functions to promote anti-viral immunity. Accumulating evidence also indicates that STING functions to promote the proinflammatory activation of several types of liver cells, especially macrophages/Kupffer cells, in a manner independent of interferon production. Over the past several years, a significant body of literature has validated a detrimental role for STING in regulating the pathogenesis of hepatic steatosis and inflammation. In particular, the STING in macrophages/Kupffer cells has attracted much attention due to its importance in not only enhancing macrophage proinflammatory activation, but also generating macrophage-derived mediators to increase hepatocyte fat deposition and proinflammatory responses, and to activate hepatic stellate cell fibrogenic activation. Both intracellular and extracellular signals are participating in STING activation in macrophages, thereby critically contributing to NAFLD phenotype. This mini review summarizes recent advances on how STING is activated in macrophages in the context of NAFLD pathophysiology.

P16 INK4A drives nonalcoholic fatty liver disease phenotypes in high fat diet fed mice through biliary E2F1/FOXO1/IGF-1 signaling.

NAFLD is characterized by steatosis, hepatic inflammation, and fibrosis, which can develop into NASH. Patients with NAFLD/NASH have increased ductular reaction (DR) and biliary senescence. High fat/high cholesterol diet feeding increases biliary senescence, DR, and biliary insulin-like growth factor-1 (IGF-1) expression in mice. p16/IGF-1 converges with fork-head box transcription factor O1 (FOXO1) through E2F1. We evaluated p16 inhibition on NAFLD phenotypes and biliary E2F1/FOXO1/IGF-1 signaling. 4-week wild-type (C57BL/6J) male mice were fed a control diet (CD) or high fat/high cholesterol diet and received either p16 or control Vivo Morpholino (VM) by tail vein injection 2× during the 16th week of feeding. We confirmed p16 knockdown and examined: (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling. Human normal, NAFLD, and NASH liver samples and isolated cholangiocytes treated with control or p16 VM were evaluated for p16/E2F1/FOXO1/IGF-1 signaling. p16 VM treatment reduced cholangiocyte and hepatocyte p16. In wild-type high fat/high cholesterol diet mice with control VM, there were increased (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling; however, p16 VM treatment reduced these parameters. Biliary E2F1/FOX-O1/IGF-1 signaling increased in human NAFLD/NASH but was blocked by p16 VM. In vitro , p16 VM reduced biliary E2f1 and Foxo1 transcription by inhibiting RNA pol II binding and E2F1 binding at the Foxo1 locus, respectively. Inhibition of E2F1 reduced biliary FOXO1 in vitro. Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.

Hypaphorine ameliorates lipid accumulation and inflammation in a cellular model of non alcoholic fatty liver by regulating p38/JNK and NF κB signaling pathways

Purpose: To investigate the therapeutic effect and underlying mechanism of hypaphorine in a cellular model of non-alcoholic fatty liver disease (NAFLD).Methods: Palmitic acid (PA) was used to induce a NAFLD phenotype in hepatocytes. Cell viability and apoptosis were evaluated by CCK-8 and flow cytometry assays. Inflammatory response was measured by enzyme-linked immunosorbent assay (ELISA). The effect of hypaphorine on lipid accumulation was evaluated using Oil Red O staining and triglyceride kits. Activation of p38/c–Jun N-terminal kinase (JNK) and NF-κB pathways were analyzed by immunoblot assay.Results: Hypaphorine significantly improved cell viability (p < 0.01), suppressed inflammatory response (p < 0.01), and reduced lipid accumulation (p < 0.01) in PA-treated hepatocytes. Hypaphorine ameliorated lipid accumulation and inflammation in PA-treated hepatocytes by targeting p38/JNK and NF-κB pathways.Conclusion: Hypaphorine may serve as a therapeutic target in NAFLD. However, in vivo studies to validate this finding are required.

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease.

To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.

Nonalcoholic Fatty Liver Disease in Lean/Nonobese and Obese Individuals: A Comprehensive Review on Prevalence, Pathogenesis, Clinical Outcomes, and Treatment.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.

Moderate Treadmill Exercise Alleviates NAFLD by Regulating the Biogenesis and Autophagy of Lipid Droplet.

Lipid droplet is a dynamic organelle that undergoes periods of biogenesis and degradation under environmental stimuli. The excessive accumulation of lipid droplets is the major characteristic of non-alcoholic fatty liver disease (NAFLD). Moderate aerobic exercise is a powerful intervention protecting against the progress of NAFLD. However, its impact on lipid droplet dynamics remains ambiguous. Mice were fed with 15 weeks of high-fat diet in order to induce NAFLD. Meanwhile, the mice performed 15 weeks of treadmill exercise. Our results showed that 15 weeks of regular moderate treadmill exercise alleviated obesity, insulin intolerance, hyperlipidemia, and hyperglycemia induced by HFD. Importantly, exercise improved histological phenotypes of NAFLD, including hepatic steatosis, inflammation, and locular ballooning, as well as prevented liver fat deposition and liver injury induced by HFD. Exercise reduced hepatic lipid droplet size, and moreover, it reduced PLIN2 protein level and increased PLIN3 protein level in the liver of HFD mice. Interestingly, our results showed that exercise did not significantly affect the gene expressions of DGAT1, DGAT2, or SEIPIN, which were involved in TG synthesis. However, it did reduce the expressions of FITM2, CIDEA, and FSP27, which were major involved in lipid droplet growth and budding, and lipid droplet expansion. In addition, exercise reduced ATGL protein level in HFD mice, and regulated lipophagy-related markers, including increasing ATG5, LAMP1, LAMP2, LAL, and CTSD, decreasing LC3II/I and p62, and promoting colocalization of LAMP1 with LDs. In summary, our data suggested that 15 weeks of moderate treadmill exercise was beneficial for regulating liver lipid droplet dynamics in HFD mice by inhibiting abnormal lipid droplets expansion and enhancing clearance of lipid droplets by lysosomes during the lipophagic process, which might provide highly flexible turnover for lipid mobilization and metabolism. Abbreviations: β-actin: actin beta; ATG5: autophagy related 5; LAMP2: lysosomal-associated membrane protein 2; LAMP1: lysosomal-associated membrane protein 1; SQSTM1/p62: sequestosome 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ATGL: adipose triglyceride lipase; CSTD: cathepsin D; LAL: lysosomal acid lipase; DGAT1: diacylglycerol-o-acyltransferase 1; DGAT2: diacylglycerol-o-acyltransferase 2; CIDEA: cell death inducing dffa-like effector a; CIDEC/FSP27: cell death inducing dffa-like effector c; FITM2: fat storage-inducing transmembrane protein 2; PLIN2: adipose differentiation related protein; PLN3: tail-interacting protein 47; HSP90: heat shock protein 90; SREBP1c: sterol regulatory element binding protein-1c; chREBP: carbohydrate response element binding protein.

An emerging probiotic with liver health benefits for smokers

Abstract Cigarette smoking is considered a risk factor for nonalcoholic fatty liver disease (NAFLD). In a study recently published in Nature, Chen et al. unveiled a mechanistic role of nicotine in NAFLD progression. In addition, they identified a gut bacterium Bacteroides xylanisolvens that can reduce intestinal nicotine levels, and thus improve nicotine-induced NAFLD phenotypes in mice.

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism.

The sugar moieties of natural flavonoids determine their absorption, bioavailability, and bioactivity in humans. To explore structure-dependent bioactivities of quercetin, isoquercetin, and rutin, which have the same basic skeleton linking different sugar moieties, we systemically investigated the ameliorative effects of dietary these flavonoids on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. Our results revealed that isoquercetin exhibits the strongest capability in improving NAFLD phenotypes of mice, including body and liver weight gain, glucose intolerance, and systemic inflammation in comparison with quercetin and rutin. At the molecular level, dietary isoquercetin markedly ameliorated liver dysfunction and host metabolic disorders in mice with NAFLD. At the microbial level, the three flavonoids compounds, especially isoquercetin, can effectively regulate the gut microbiota composition, such as genera Akkermansia, Bifidobacterium, and Lactobacillus, which were significantly disrupted in NAFLD mice. These comparative findings offer new insights into the structure-dependent activities of natural flavonoids for NAFLD treatment.

Offspring NAFLD liver phospholipid profiles are differentially programmed by maternal high-fat diet and maternal one carbon supplement

Little is known if and how maternal diet affects the liver phospholipid profiles that contribute to non-alcoholic fatty liver disease (NAFLD) development in offspring. We examined NAFLD phenotypes in male offspring mice of either maternal normal-fat diet (NF group), maternal high-fat diet (HF group), maternal methionine supplement (H1S group), or complete one-carbon supplement (H2S group) added to the maternal HF diet during gestation and lactation. HF offspring displayed worsened NAFLD phenotypes induced by post-weaning HF diet, however, maternal one-carbon supplement prevented such outcome. HF offspring also showed a distinct phospholipid profile from the offspring exposed to H1S or H2S diet. Whole genome bisulfite sequencing (WGBS) analysis further identified five pathways involved in phospholipid metabolism altered by different maternal diet interventions. Furthermore, differential methylated regions (DMRs) on Prkca, Dgkh, Plcb1 and Dgki were identified comparing between HF and NF offspring; most of these DMRs were recovered in H2S offspring. These methylation pattern changes were associated with gene expression changes: HF diet significantly reduced while H1S and H2S diet recovered their levels. Maternal HF diet disrupted offspring phospholipid profiles contributing to worsened hepatic steatosis. The maternal one-carbon supplement prevented such effects, probably through DNA methylation modification.

Deletion of adipocyte prohibitin 1 exacerbates high-fat diet-induced steatosis but not liver inflammation and fibrosis.

Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin-1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The PHB1 protein levels in adipose tissues were markedly decreased in mice fed a high-fat diet (HFD) compared to those fed a chow diet. To explore the function of adipocyte PHB1 in the progression of NAFLD, mice with adipocyte-specific (adipo) deletion of Phb1 (Phb1adipo-/- mice) were generated. Notably, Phb1adipo-/- mice did not develop obesity but displayed severe liver steatosis under HFD feeding. Compared to HFD-fed wild-type (WT) mice, HFD-fed Phb1adipo-/- mice displayed dramatically lower fat mass with significantly decreased levels of total adipose tissue inflammation, including macrophage and neutrophil number as well as the expression of inflammatory mediators. To our surprise, although liver steatosis in Phb1adipo-/- mice was much more severe, liver inflammation and fibrosis were similar to WT mice after HFD feeding. RNA sequencing analyses revealed that the interferon pathway was markedly suppressed while the bone morphogenetic protein 2 pathway was significantly up-regulated in the liver of HFD-fed Phb1adipo-/- mice compared with HFD-fed WT mice. Conclusion: HFD-fed Phb1adipo-/- mice display a subtype of the lean NAFLD phenotype with severe hepatic steatosis despite low adipose mass. This subtype of the lean NAFLD phenotype has similar inflammation and fibrosis as obese NAFLD in HFD-fed WT mice; this is partially due to reduced total adipose tissue inflammation and the hepatic interferon pathway.

S1185 Mortality in Patients With Lean NAFLD: A Systematic Review and Meta-Analysis

Introduction: While obesity is highly contributory to the development of nonalcoholic fatty liver disease (NAFLD), around 40% of patients with NAFLD are non-obese or lean. However, clinical outcomes of lean NAFLD are not well described, and the magnitude of the risk of mortality in lean patients with NAFLD compared to those who are non-lean remains uncertain. Methods: PubMed, Embase, and Cochrane library database were searched from inception to May 28, 2022 to identify eligible cohort studies assessing the risk of mortality among lean and non-lean patients with NAFLD. Meta-analysis was performed using random-effects models to obtain pooled relative risks (RRs) with 95% confidence intervals (CIs). Heterogeneity between studies was calculated using the Cochran Q test and I statistics. Results: Ten cohort studies with 109,151 patients with NAFLD were included. Patients with lean NAFLD had a comparable risk of all-cause mortality (RR, 1.09; 95% CI, 0.67 to 1.77; I-squared, 97.7%) and cardiovascular disease-specific mortality (RR, 1.12; 95% CI, 0.66 to 1.90; I-squared, 86.2%) to those with non-lean NAFLD. The pooled risk of liver disease-specific mortality was 1.88 times (RR; 95% CI, 1.02 to 3.45; I-squared, 29.4%) higher in patients with lean NAFLD. Conclusion: In patients with NAFLD, lean individuals have a higher risk of liver disease-specific mortality than non-lean individuals, however, the risk of all-cause mortality and cardiovascular mortality did not differ among the two groups. Further understanding of the risk factors, genetic and ethnic variabilities, and metabolic process of lean NAFLD phenotype is warranted. Furthermore, research is needed to determine mechanisms on how lean NAFLD is associated with worse liver mortality and to develop individualized treatment strategies for patients with lean NAFLD.Figure 1.: Comparative risk of all-cause mortality in lean and non-lean patients with NAFLD.

Ancestral BPA exposure caused defects in the liver of medaka for four generations

Environmental chemicals can induce liver defects in experimental animals due to their direct and acute exposure. It is not clear whether environmental chemical exposures result in the transgenerational passage of liver defects in subsequent generations living in an uncontaminated environment. Bisphenol A (BPA), a plasticizer chemical, has been ubiquitous in the environment in the recent decade. Every organism is exposed to this chemical at some point during its lifetime. Literature suggests that direct BPA exposure can result in several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Despite the phasing out of BPA from several consumer goods, it is unclear whether ancestral BPA exposure causes liver health problems in the unexposed future generations. Here, we demonstrate an advanced stage of NAFLD in the grandchildren (F2 generation) of medaka fish (Oryzias latipes) due to embryonic BPA exposure in the grandparental generation (F0), which persists for five generations (F4) even in the absence of BPA. The severity of transgenerational NAFLD phenotype included steatosis together with perisinusoidal fibrosis and apoptosis of hepatocytes. Adult females developed more severe histopathological conditions in the liver than males. Genes encoding enzymes involved in lipolytic pathways were significantly decreased. The present results suggest that ancestral BPA exposure can result in transgenerational metabolic diseases that can persist for five generations and that the NAFLD trait is sexually dimorphic. Given that ancestral BPA exposure can lead to altered metabolic health outcomes in the subsequent unexposed generations, the development of the methods and strategies to mitigate the transgenerational onset of metabolic diseases seem imperative to protect future generations.

Hepatocellular carcinoma surveillance in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhotic or non-cirrhotic hepatocellular carcinoma (HCC), and is currently recognized as the fastest growing cause of HCC worldwide. Accordingly, professional society guidelines recommend HCC surveillance in patients with cirrhosis from any etiology, and some may consider it beneficial in subgroups with non-cirrhotic NAFLD at higher risk for HCC. Notably, patients with NAFLD-related HCC are more likely to have HCC diagnosed at more advanced stages and have poorer outcomes when compared to other etiologies, and suboptimal effectiveness of HCC surveillance programs is a major culprit. In this review, we summarize the current guidelines for HCC surveillance and discuss its benefits versus potential harms for NAFLD patients. We also address the unique challenges of HCC surveillance in NAFLD, including higher proportion of NAFLD-related HCC without cirrhosis, poor recognition of at-risk patients, lack of consensus regarding the value of surveillance in non-cirrhotic NAFLD, subpar effectiveness of surveillance tools related to NAFLD phenotype, and preponderant surveillance underuse among NAFLD patients. Finally, we examine the effectiveness of currently used surveillance tools (i.e., ultrasound and alpha fetoprotein) and outline future perspectives including emerging risk stratification tools, imaging surveillance strategies (e.g., abbreviated magnetic resonance imaging protocols), blood-based biomarkers (e.g., GALAD and circulating tumor DNA panels), and interventions to improve surveillance adherence.

IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease

A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD. To enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development. Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity. Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD. An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.

Antioxidants Rich Herbal Formula Ger-Gen-Chyn-Lian-Tang Protects Lipotoxicity and Ameliorates Inflammation Signaling through Regulation of Mitochondrial Biogenesis and Mitophagy in Nonalcoholic Fatty Liver Disease Mice.

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent issue and a consequence of metabolic syndrome impact on human health. Both of anti-atherosclerosis and anti-hepatic fibrosis capabilities of herbal medicine Ger-Gen-Chyn-Lian-Tang (GGCLT) has attracted attention, but their molecular regulatory mechanisms in a NAFLD model have not been elucidated. The aim of the present study was to explore the bioactivity of db/db mice following treatment with GGCLT. NAFLD phenotype of db/db mice were treated with GGCLT and lipogenesis, mitochondria dysfunction, mitophagy, macrophage polarization and adipose tissue browning were then evaluated using qRT-PCR and/or Western blot analysis, immunofluorescence, and immunohistochemistry assays, respectively. GGCLT not only decreased serum levels of TG and free fatty acids, but glucose and insulin tolerance test in db/db mice. In parallel, GGCLT reduced lipogenesis and hypoxia-inflammation cascades in NAFLD progression. GGCLT reduced lipid accumulation and was accompanied by the enhanced mitochondria biogenesis, M2 macrophage, and decreased M1 macrophage. The latter two events contributing to the anti-inflammation are resulting from mitochondria dynamics, and the lipotoxicity lowering effect of GGCLT of NAFLD mice is mediated by promoting mitophagy in Parkin-dependent and -independent pathways, by mitochondrial fusion over fission manner. GGCLT also inactivated lipogenesis and decreased lipid accumulation in epididymal white adipose tissue with a higher M2/M1 macrophage ratio. Besides in the liver, modulating of mitochondrial biogenesis and adipose tissue browning were characterized by increased Tmem26, Tfam, and Prdm16 expression by GGCLT in EWAT also contributes to the beneficial action in NAFLD.

HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease.

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.