Etiology Of Nonalcoholic Fatty Liver Disease Research Articles

Identifying potential drug targets for non-alcoholic fatty liver disease: a drug target Mendelian randomization study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK Research and Innovation Training Grant: Centre for Doctoral Training in AI-enabled Healthcare Systems Background Non-alcoholic fatty liver disease (NAFLD), a range of conditions caused by the build-up of fat in the liver, is the most common form of chronic liver disease, with an estimated prevalence of ~25% globally. NAFLD is associated with increased risk of all-cause mortality, with CVD emerging as the primary cause of death amongst affected individuals. The aetiology of NAFLD is not yet clearly understood, and currently no drugs exist for its treatment, with therapeutics aimed at symptom management instead. Purpose To identify and prioritise candidate protein drug targets and pathways relevant for therapeutic intervention in NAFLD. Methods To identify plasma proteins causally associated with NAFLD, we analysed genetic associations on 1,561 proteins from 35,559 participants in the deCODE study, and compared these to associations from a GWAS of biopsy confirmed NAFLD cases (1,483 cases, 17,781 controls). We sourced genetic variants from a 400kbp region around each protein-coding gene, pruning variants on an F-statistic of 15, minor allele frequency threshold of 1% and linkage disequilibrium r-squared of 0.4. cis-Mendelian randomization (MR) was used to identify proteins associated with NAFLD. Bias due to pleiotropy was limited by excluding variants with leverage statistic more than 3 times the mean, or outlier statistic larger than 10.83. We used colocalization analysis to identify proteins with a posterior probability of at least 0.8, indicating the presence of common causal variants. We further prioritised proteins by annotating them with information on druggability (i.e. whether a protein is a target for a known drug, or predicted to be a target for a drug), mRNA expression in pathology-relevant tissues, and involvement in known biological pathways. Results We identified 5 proteins with a multiplicity-corrected (p<3.2×10-5) association with NAFLD, and strong evidence of genetic colocalization: CYB5A, NT5C, NCAN, TGFBI, DAPK2. TGFBI and DAPK2 are potentially druggable, with all five found to be expressed in both liver and adipose tissues. Pathway analysis indicated the involvement of NT5C, CYB5A, NCAN in Reactome pathway R-HSA-1430728 reflecting cellular energy metabolism, including mitochondrial lipid metabolism, which is strongly implicated with NAFLD. Conclusion We identified a prioritised set of five plasma proteins influencing NAFLD, including druggable proteins informing de novo and ongoing drug development programs. Figure: MR effect estimates of proteins on NAFLD A: Effect of each protein on NAFLD. Each point represents a protein, effect estimates are reported in log(odds ratio) and statistical significance in -log(p-value). Coloured points represent proteins passing the multiplicity-corrected p-value threshold B: MR effect estimates of prioritised proteins. Estimates are reported in log(odds ratio). Proteins are annotated according to their druggability based on the British National Formulary and ChEMBL

Crosstalk in extrahepatic and hepatic system in NAFLD/NASH.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non-alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter-organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra- and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver-gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra-hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH.

Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study.

The prevalence of non-alcoholic fatty liver disease (NAFLD) in U.S. adults is over 30%, yet the role of lifestyle factors in the etiology of NAFLD remains understudied. We examined the associations of physical activity, by intensity and type, and television viewing with prevalent NAFLD. Cross-sectional analysis of a population-based sample of 2726 Black (49%) and White (51%) adults (Mean (SD) age, 50 (3.6) years; 57.3% female) from the CARDIA study. Exposures were aerobic activity by intensity (moderate, vigorous; hours/week); activity type (aerobic, muscle-strengthening; hours/week); and television viewing (hours/week), examined concurrently in all models and assessed by validated questionnaires. Our outcome was NAFLD (liver attenuation < 51 Hounsfield Units), measured by non-contrast computed tomography, after exclusions for other causes of liver fat. Covariates were sex, age, race, study center, education, diet quality, smoking status, alcohol consumption, and body mass index or waist circumference. 648 participants had NAFLD. In the fully adjusted modified Poisson regression model, the risk ratios per interquartile range of each exposure were moderate-intensity aerobic activity, 1.10 (95% CI, 0.97-1.26); vigorous-intensity aerobic activity, 0.72 (0.63-0.82); muscle-strengthening activity, 0.89 (0.80-1.01); and television viewing, 1.20 (1.10-1.32). Relative to less active participants with higher levels of television viewing, those who participated in ≥2 h/week of both vigorous-intensity aerobic and muscle-strengthening activity and <7 h/week of television viewing had 65% lower risk of NAFLD (risk ratio = 0.35, 95% CI = 0.23-0.51). Adults who follow public health recommendations for vigorous-aerobic and muscle-strengthening activity, as well as minimize television viewing, are considerably less likely to have NAFLD than those who do not follow the recommendations and who have relatively high levels of television viewing.

Short-term high-fat diet feeding of mice suppresses catecholamine-stimulated Ca2+ signalling in hepatocytes and intact liver.

Excess consumption of carbohydrates, fat and calories leads to non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; these are major factors in the pathogenesis of type II diabetes. Hormones and catecholamines acting through G-protein coupled receptors (GPCRs) linked to phospholipase C (PLC) and increases in cytosolic Ca2+ ([Ca2+ ]c ) regulate many metabolic functions of the liver. In the intact liver, catabolic hormones such as glucagon, catecholamines and vasopressin integrate and synergize to regulate the frequency and extent to which [Ca2+ ]c waves propagate across hepatic lobules to control metabolism. Dysregulation of hepatic Ca2+ homeostasis has been implicated in the development of metabolic disease, but changes in hepatic GPCR-dependent Ca2+ signalling have been largely unexplored in this context. We show that short-term, 1-week, high-fat diet (HFD) feeding of mice attenuates noradrenaline-stimulated Ca2+ signalling, reducing the number of cells responding and suppressing the frequency of [Ca2+ ]c oscillations in both isolated hepatocytes and intact liver. The 1-week HFD feeding paradigm did not change basal Ca2+ homeostasis; endoplasmic reticulum Ca2+ load, store-operated Ca2+ entry and plasma membrane Ca2+ pump activity were unchanged compared to low-fat diet (LFD)-fed controls. However, noradrenaline-induced inositol 1,4,5-trisphosphate production was significantly reduced after HFD feeding, demonstrating an effect of HFD on receptor-stimulated PLC activity. Thus, we have identified a lesion in the PLC signalling pathway induced by short-term HFD feeding, which interferes with hormonal Ca2+ signalling in isolated hepatocytes and the intact liver. These early events may drive adaptive changes in signalling, which lead to pathological consequences in fatty liver disease. KEY POINTS: Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic. In healthy liver, the counteracting effects of catabolic and anabolic hormones regulate metabolism and energy storage as fat. Hormones and catecholamines promote catabolic metabolism via increases in cytosolic Ca2+ ([Ca2+ ]c ). We show that 1week high-fat diet (HFD) feeding of mice attenuated the Ca2+ signals induced by physiological concentrations of noradrenaline. Specifically, HFD suppressed the normal pattern of periodic [Ca2+ ]c oscillations in isolated hepatocytes and disrupted the propagation of intralobular [Ca2+ ]c waves in the intact perfused liver. Short-term HFD inhibited noradrenaline-induced inositol 1,4,5-trisphosphate generation, but did not change basal endoplasmic reticulum Ca2+ load or plasma membrane Ca2+ fluxes. We propose that impaired Ca2+ signalling plays a key role in the earliest phases of the etiology of NAFLD, and is responsible for many of the ensuing metabolic and related dysfunctional outcomes at the cellular and whole tissue level.

Ferroptosis in non-alcoholic liver disease: Molecular mechanisms and therapeutic implications.

Ferroptosis refers to a novel modality of regulated cell death characterized by excessive iron accumulation and overwhelming lipid peroxidation, which takes an important part in multiple pathological processes associated with cell death. Considering the crucial roles of the liver in iron and lipid metabolism and its predisposition to oxidative insults, more and more studies have been conducted to explore the relationship between ferroptosis and various liver disorders, including non-alcoholic fatty liver disease (NAFLD). With increased morbidity and high mortality rates, NAFLD has currently emerged as a global public health issue. However, the etiology of NAFLD is not fully understood. In recent years, an accumulating body of evidence have suggested that ferroptosis plays a pivotal role in the pathogenesis of NAFLD, but the precise mechanisms underlying how ferroptosis affects NAFLD still remain obscure. Here, we summarize the molecular mechanisms of ferroptosis and its complicated regulation systems, delineate the different effects that ferroptosis exerts in different stages of NAFLD, and discuss some potential effective therapies targeting ferroptosis for NAFLD treatment, which putatively points out a novel direction for NAFLD treatment.

Beneficial Effect of Vitamin D on Non-Alcoholic Fatty Liver Disease (NAFLD) Progression in the Zebrafish Model

A major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) results from excessive liver fat accumulation. Vitamin D (VitD) plays multiple important roles in diverse physiologic processes. Here, we describe the role of VitD in the complex pathogenesis of NAFLD and explore the possible therapeutic role of VitD supplementation in NAFLD therapy. To compare the effect of VitD to other interventions such as low-calorie diet, we induced NAFLD in young adult zebrafish (Danio rerio, AB strain) and monitored the effects of VitD supplementation on the disease course. The zebrafish administered with high-dose VitD (1.25 μg) had significantly reduced liver fat compared to those that received low-dose VitD (0.049 μg) or caloric restriction. Gene expression analysis revealed that VitD downregulated several pathways that may play a role in NAFLD etiology, which affected fatty acid metabolism, vitamins and their cofactors, ethanol oxidation, and glycolysis. The pathway analysis revealed that the cholesterol biosynthesis pathway and the isoprenoid biosynthetic process pathway were significantly upregulated whereas the small molecule catabolic process pathway significantly downregulated following the exposure of NAFLD zebrafish model to high VitD dose. Therefore, our findings suggest the association of novel biochemical pathways with NAFLD and highlight the potential of VitD supplementation to reverse the severity of NAFLD, especially in younger people.

Natural Foods for the Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The etiology of NAFLD is highly heterogeneous, which occurs and develops under the joint action of metabolism, inflammation, genetics, environment, and gut microbiota. At present, the principal therapeutic modalities targeting NAFLD are lifestyle interventions such as weight loss through diet and exercise. At present, there is no established therapy for the treatment of NAFLD, and many therapies are associated with a variety of side effects. A great number of in vitro and in vivo experiments have indicated that there are many natural foods that have therapeutic potential for NAFLD. This review summarizes the natural foods and their mechanisms that were found in recent years, furthermore, provides further information relevant to the treatment of NAFLD.

Epigenetic association study uncovered H3K27 acetylation enhancers and dysregulated genes in high-fat-diet-induced nonalcoholic fatty liver disease in rats.

Aim: To evaluate the regulatory landscape underlying the active enhancer marked by H3K27ac in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in rats. Materials & methods: H3K27ac chromatin immunoprecipitation and high-throughput RNA sequencing to construct regulatory profiles and transcriptome of liver from NAFLD rat model induced by HFD. De novo motif analysis for differential H3K27ac peaks. Functional enrichment, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction network were examined for differential peak-genes. The mechanism was further verified by western blot, chromatin immunoprecipitation-quantitativePCR and real-timePCR. Results:A total of1831 differential H3K27ac peaks were identified significantly correlating with transcription factors and targetgenes (CYP8B1, PLA2G12B, SLC27A5, CYP7A1 and APOC3) involved in lipid and energy homeostasis. Conclusion: Altered acetylation induced by HFD leads to the dysregulation of gene expression, further elucidating the epigenetic mechanism in the etiology of NAFLD.

Healthcare Costs for Medicare Patients With Hepatocellular Carcinoma in the United States

Hepatocellular carcinoma (HCC) has an increasing mortality in the United States and is a leading cause of morbidity and mortality in patients with cirrhosis. We aimed to estimate the financial burden related to HCC in a large nationally representative United States cohort. We used the Surveillance, Epidemiology, and End Results program (SEER)-Medicare database to identify 4525 adult patients who were diagnosed with HCC between 2011 and 2015. We generated a 1:1 propensity score-matched cohort of patients with cirrhosis but no HCC as a comparator group to define incremental HCC-specific costs beyond costs related to underlying cirrhosis. Our main outcomes were patient liabilities and Medicare payments in the first year after HCC diagnosis. Compared with patients with cirrhosis, those with HCC had higher incremental patient liabilities (median+$7166; interquartile range, $2401-$16,099) and Medicare payments (+$50,110; interquartile range, $142,42-$136,239; P < .001 for both) in the first year after diagnosis. Patients with HCC had significantly higher inpatient, outpatient, and physician service costs compared with the matched cohort with cirrhosis (P < .001 for all). Patients with early-stage HCC had lower incremental patient liabilities (median, $4195 vs $8238; P < .001) and Medicare payments (median, $28,207 vs $59,509; P < .001) than those with larger tumor burden. In multivariable median regression analysis, incremental patient liabilities and Medicare payments were significantly associated with the National Cancer Institute comorbidity index, nonalcoholic fatty liver disease etiology, presence of ascites, and presence of hepatic encephalopathy. Patients with HCC suffer from cancer-related financial burden, highlighting a need for policy interventions and financial support systems.

Redistribution of lamina-associated domains reshapes binding of pioneer factor FOXA2 in development of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We previously showed that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and up-regulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here, we test the hypothesis that change in the expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2 and by up-regulation of lipid synthesis and storage, culminating in steatosis in younger NAFLD patients (aged 21-51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlate with increased FOXA2 binding before severe steatosis in young mice placed on a western diet. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.

Global landscape of protein complexes in postprandial-state livers from diet-induced obese and lean mice

Obesity is associated with a spectrum of nonalcoholic fatty liver disease (NAFLD) which is characterized by steatosis. Prolonged fat deposition aggravates liver dysfunctions leading to an advanced form of NAFLD such as steatohepatitis and cirrhosis. As liver function in the postprandial state is critical for macronutrient metabolism and energy homeostasis, we sought to determine the differences in protein complex profiles in lean and fatty livers in the postprandial state. Protein complex profiling is of interest as proteins often do not function alone and the information on the interactions may reveal novel etiology of NAFLD, which is currently limited compared with proteome profiles or RNA-sequencing profiles. To this end, we fractionated liver lysates using size-exclusion chromatography (SEC) and analyzed each fraction using untargeted LC-MS/MS. We identified 1172 proteins that were discovered in lean and fatty livers, and their elution profiles were compared. We found that the majority of liver proteins were present as putative complexes. Also, the fatty liver protein elution profile showed great conservations as lean liver despite the metabolic disease state. Yet, we discovered a few proteins that showed different elution patterns in the fatty liver, including Acadm, Aldh1a7, Aldh1a1, Akr1a1, Eif3l, Fkbp2, G6pdx, Gm20441, Hao1, Pcna, Pkm, Ppif, Prdx4, Stmn1, Tagln, Tubb4b, Ubqln2, and Usp14, which may be involved in high fat diet-induced alterations of protein oligomerization and hepatic functions. Overall, our protein complex profiling could expand our understanding of hepatic abnormalities that cannot be uncovered by simple quantitation of protein expression.

Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease.

BackgroundInflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive.ObjectiveThis study aimed to evaluate the association between inflammatory cytokines and NAFLD.MethodsPubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out.ResultsThe search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis.ConclusionsOur results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.

Growth Hormone and Insulin-Like Growth Factor 1 Regulation of Nonalcoholic Fatty Liver Disease.

Patients with obesity have a high prevalence of nonalcoholic fatty liver disease (NAFLD), representing a spectrum of simple steatosis to nonalcoholic steatohepatitis (NASH), without and with fibrosis. Understanding the etiology of NAFLD is clinically relevant since NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, NASH predisposes patients to the development of cirrhosis and hepatocellular carcinoma, and NASH cirrhosis represents the fastest growing indication for liver transplantation in the United States. It is appreciated that multiple factors are involved in the development and progression of NAFLD. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) regulate metabolic, immune, and hepatic stellate cell function, and alterations in the production and function of GH is associated with obesity and NAFLD/NASH. Therefore, this review will focus on the potential role of GH and IGF1 in the regulation of hepatic steatosis, inflammation, and fibrosis.

Metabolism and Health Effects of Rare Sugars in a CACO-2/HepG2 Coculture Model.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide and is impacted by an unhealthy diet with excessive calories, although the role of sugars in NAFLD etiology remains largely unexplored. Rare sugars are natural sugars with alternative monomers and glycosidic bonds, which have attracted attention as sugar replacers due to developments in enzyme engineering and hence an increased availability. We studied the impact of (rare) sugars on energy production, liver cell physiology and gene expression in human intestinal colorectal adenocarcinoma (Caco-2) cells, hepatoma G2 (HepG2) liver cells and a coculture model with these cells. Fat accumulation was investigated in the presence of an oleic/palmitic acid mixture. Glucose, fructose and galactose, but not mannose, l-arabinose, xylose and ribose enhanced hepatic fat accumulation in a HepG2 monoculture. In the coculture model, there was a non-significant trend (p = 0.08) towards higher (20–55% increased) median fat accumulation with maltose, kojibiose and nigerose. In this coculture model, cellular energy production was increased by glucose, maltose, kojibiose and nigerose, but not by trehalose. Furthermore, glucose, fructose and l-arabinose affected gene expression in a sugar-specific way in coculture HepG2 cells. These findings indicate that sugars provide structure-specific effects on cellular energy production, hepatic fat accumulation and gene expression, suggesting a health potential for trehalose and l-arabinose, as well as a differential impact of sugars beyond the distinction of conventional and rare sugars.

An Efficient Model of Non-alcoholic Fatty Liver Disease (NAFLD) Versus Current Experimental Models: Effects of Fructose, Fat, and Carbon Tetrachloride on NAFLD

Background: Accumulation of fat in the liver is one of the causes of non-alcoholic fatty liver disease (NAFLD), which affects about 30% of the world's population. Animal models have been useful tools for investigating the mechanisms involved in the etiology of NAFLD and developing new drugs. Objectives: This study aimed to present a new model for the detection of NAFLD in rats. Methods: Forty-eight rats were randomly divided into six experimental groups: (1) control; (2) 45% fructose + 35% olive oil + carbon tetrachloride (FFC1); (3) carbon tetrachloride (1: 4 in olive oil) (C1); (4) carbon tetrachloride (1: 6 in olive oil) (C2); (5) 12.5% fructose + 12.5% olive oil (FF); and (6) 20% fructose + carbon tetrachloride (1: 4 in olive oil) (FC1). Blood samples were taken in three steps, and liver tissue was dissected at the end of the sixth week for histopathological assessments. Results: After six weeks, the alanine transaminase (131.63 ± 1.51), aspartate transaminase (275 ± 1.0), and gamma-glutamyl transferase (4.30 ± 0.1) levels increased significantly in the C1 group (P &lt; 0.05). The serum lipid profile showed significant changes in all groups compared to the controls (P &lt; 0.01). According to the histological results, all experimental groups, except the C2 group, showed symptoms of NAFLD; nevertheless, a higher NAFLD Activity Score (NAS) was found in the C1 group, followed by the FC1 group, compared to the other groups. Conclusions: The present results revealed that injection of 0.1 mL/kg of carbon tetrachloride (C1 group), alone or along with a diet containing 20% fructose (FC1 group), provided useful animal models of NAFLD, although carbon tetrachloride injection alone is the most effective model in inducing NAFLD model that can be used as a new strategy in nutritional and pharmacological studies.

Greater liver PNPLA3 protein abundance in vivo and in vitro supports lower triglyceride accumulation in dairy cows

Fatty liver syndrome is a prevalent metabolic disorder in peripartum dairy cows that unfavorably impacts lactation performance and health. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipase that plays a central role in human non-alcoholic fatty liver disease etiology but has received limited attention in bovine fatty liver research. Thus, we investigated the relationship between tissue PNPLA3 expression and liver triglyceride accumulation in vivo via a ketosis induction protocol in multiparous dairy cows peripartum, as well as in vitro via small interfering RNA knockdown of PNPLA3 mRNA expression in bovine primary hepatocytes. Results demonstrated a negative association (P = 0.04) between liver PNPLA3 protein abundance and liver triglyceride content in peripartum dairy cows, while adipose PNPLA3 protein abundance was not associated with liver triglyceride content or blood fatty acid concentration. Knockdown of PNPLA3 mRNA resulted in reduced PNPLA3 protein abundance (P < 0.01) and greater liver triglyceride content (P < 0.01). Together, these results suggest greater liver PNPLA3 protein abundance may directly limit liver triglyceride accumulation peripartum, potentially preventing bovine fatty liver or accelerating recovery from fatty liver syndrome.

The Role of Life Style Modifications in Comprehensive Non-Alcoholic Fatty Liver Disease Treatment.

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Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants.

Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.

Potential targets for prevention and treatment of non-alcoholic fatty liver disease in adults

Non-alcoholic fatty liver disease (NAFLD) is a common condition worldwide contributing to serious liver disorders like hepatic fibrosis and hepatocellular carcinoma. Most common of NAFLD etiology is a sedentary lifestyle and taking a high-calorie diet. Presently there is no drug available for the treatment of NAFLD and only dietary measures, increased physical activity and exercise, antioxidants are the options. In this review, detailed pathophysiology, diagnostic methods and potential targets for prevention and timely treatment of NAFLD have been described.

Development of a Chicken Model of Nonalcoholic Fatty Liver Disease Induced by High Cholesterol and Low Choline Diet

Non‐alcoholic fatty liver disease (NAFLD), a most common liver disease in human, is one of the primary causes of the laying hen death in chicken farming. It leads to a great commercial loss in agricultural sector. Therefore, reliable chicken models of NAFLD is required for the research of NAFLD etiology and prevention in chickens. To generate rapid chicken models of NAFLD, 7‐week‐old ISA chickens were fed with control diet (18% dietary protein, 4.72% fat, and 1300 mg/kg choline), low protein and high fat diet (LPHF, 13% dietary protein, 8.95% fat, and 1300 mg/kg choline), high cholesterol with low choline diet (CLC, 18% dietary protein, 4.72% fat, 2% cholesterol, and 800 mg/kg choline), or low protein, high fat, low choline, and high cholesterol diet (LPHFCLC, 13% CP, 8.95% fat, 2% cholesterol, and 800 mg/kg choline) for 4 weeks. Compared with control group, CLC and LPHFCLC treatments significantly elevated the level of plasma triglyceride and cholesterol. The appearance and the histological sections of the livers showed that CLC and LPHFCLC treatments significantly led to the accumulation of fat in the livers. The symptoms of steatohepatitis, hepatic ballooning and immune infiltration, were presented in the livers in CLC and LPHFCLC groups. In addition, the levels of dipeptidyl‐peptidase 4, a biomarker of fatty liver hemorrhagic syndrome in laying hens, were also increased in the plasma of CLC and LPHFCLC treatments. These data indicated that the diet with 2% cholesterol and 800 mg/kg choline was sufficient to induce hepatic steatosis and steatohepatitis. Moreover, the genes related to lipogenesis (PPARG, SREBP1C, and FASN) and pro‐inflammation cytokines (TNFA and IL1B) were elevated in the CLC group, further confirming the effects of CLC treatment on laying hens. Interestingly, CLC treatment also induced non‐alcoholic fatty livers in Plymouth Rock broiler chickens. It suggested that CLC treatment may induce non‐alcoholic fatty liver disease in different strains of chickens. Therefore, our data suggested that CLC treatment may induced rapid and reliable non‐alcoholic fatty liver disease in chickens. Accordingly, de novo lipogenesis is primary occurred in the livers both in chicken and human. This model can be expected to be utilized for the screening of functional components to prevent or improve fatty livers in chickens and human.