Liver Function In Adults Research Articles

Effects of l-carnitine on frailty status in patients with liver cirrhosis: A randomized-controlled trial.

Frailty is a common complication in patients with liver cirrhosis, which is linked with augmented rates of morbidity and mortality. In this regard, timely nutritional assessment and intervention have gained scientific attention. L-carnitine may be a promising candidate with its potential to enhance energy metabolism, reduce inflammation, and act as an antioxidant. Therefore, we aimed to assess the impact of l-carnitine supplementation on frailty status and liver function in adults with liver cirrhosis. This double-blinded, randomized, controlled clinical trial study enrolled 77 patients with liver cirrhosis. Patients were randomly allocated into two groups: the control group (n = 42) and the l-carnitine group (n = 35). The l-carnitine group received 500 mg of l-carnitine orally three times a day for 8 weeks, while the control group did not receive any intervention. L-carnitine administration resulted in a significant decrease in alanine transaminase levels (p: 0.043) and partial thromboplastin time (p: 0.036). Furthermore, compared to the control group, l-carnitine treatment led to improvements in prothrombin time (p: 0.008) and international normalized ratio (p: 0.024). However, no significant improvement in the Liver Frailty Index, Freid Frailty Index, and Karnofsky Performance Status Scale (p > 0.05) was observed in the carnitine group after the 8-week intervention period. In conclusion, the administration of l-carnitine exhibited hepatoprotective properties and was correlated with lowered alanine transaminaselevels with improvement in coagulation status in liver cirrhosis patients. Nevertheless, our study indicated that the short-term use of l-carnitine might not significantly improve frailty in these patients.

Generation and characterization of mature hepatocyte organoids for liver metabolic studies.

Hepatocyte organoids (HOs) generated in vitro are powerful tools for liver regeneration. However, previously reported HOs have mostly been fetal in nature with low expression levels of metabolic genes characteristic of adult liver functions, hampering their application in studies of metabolic regulation and therapeutic testing for liver disorders. Here, we report development of novel culture conditions that combine optimized levels of triiodothyronine (T3) with the removal of growth factors to enable successful generation of mature hepatocyte organoids (MHOs) of both mouse and human origin with metabolic functions characteristic of adult livers. We show that the MHOs can be used to study various metabolic functions including bile and urea production, zonal metabolic gene expression, and metabolic alterations in both alcoholic liver disease and non-alcoholic fatty liver disease, as well as hepatocyte proliferation, injury and cell fate changes. Notably, MHOs derived from human fetal hepatocytes also show improved hepatitis B virus infection. Therefore, these MHOs provide a powerful in vitro model for studies of human liver physiology and diseases. The human MHOs are potentially also a robust research tool for therapeutic development.

A Narrative Review on Maternal Choline Intake and Liver Function of the Fetus and the Infant; Implications for Research, Policy, and Practice.

Dietary choline is needed to maintain normal health, including normal liver function in adults. Fatty liver induced by a choline-deficient diet has been consistently observed in human and animal studies. The effect of insufficient choline intake on hepatic fat accumulation is specific and reversible when choline is added to the diet. Choline requirements are higher in women during pregnancy and lactation than in young non-pregnant women. We reviewed the evidence on whether choline derived from the maternal diet is necessary for maintaining normal liver function in the fetus and breastfed infants. Studies have shown that choline from the maternal diet is actively transferred to the placenta, fetal liver, and human milk. This maternal-to-child gradient can cause depletion of maternal choline stores and increase the susceptibility of the mother to fatty liver. Removing choline from the diet of pregnant rats causes fatty liver both in the mother and the fetus. The severity of fatty liver in the offspring was found to correspond to the severity of fatty liver in the respective mothers and to the duration of feeding the choline-deficient diet to the mother. The contribution of maternal choline intake in normal liver function of the offspring can be explained by the role of phosphatidylcholine in lipid transport and as a component of cell membranes and the function of choline as a methyl donor that enables synthesis of phosphatidylcholine in the liver. Additional evidence is needed on the effect of choline intake during pregnancy and lactation on health outcomes in the fetus and infant. Most pregnant and lactating women are currently not achieving the adequate intake level of choline through the diet. Therefore, public health policies are needed to ensure sufficient choline intake through adding choline to maternal multivitamin supplements.

Independent and combined associations of urinary metals exposure with markers of liver injury: Results from the NHANES 2013–2016

BackgroundHeavy metals entering the human body could cause damage to a variety of organs. However, the combined harmful effects of exposure to various metals on liver function are not well understood. The purpose of the study was to investigate the independent and joint relationships between heavy metal exposure and liver function in adults. MethodsThe study involved 3589 adults from the National Health and Nutrition Examination Survey. Concentrations of urinary metals, including arsenic (As), cadmium (Cd), lead (Pb), antimony (Sb), barium (Ba), thallium (Tl), tungsten (W), uranium (U), were determined in urine using inductively coupled plasma mass spectrometry. Data for liver function biomarkers included alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transaminase (GGT), and alkaline phosphatase (ALP). Survey-weighted linear regression and quantile g-computation (qgcomp) were employed to evaluate the relationship of urinary metals with the markers of liver injury. ResultsCd, U and Ba were found to have positive correlations with ALT, AST, GGT, and ALP in the survey-weighted linear regression analyses. According to the qgcomp analyses, the total metal mixture was positively correlated with ALT (percent change: 8.15; 95% CI: 3.84, 12.64), AST (percent change: 5.55; 95% CI: 2.39, 8.82), GGT (percent change: 14.30; 95% CI: 7.81, 21.18), and ALP (percent change: 5.59; 95% CI: 2.65, 8.62), and Cd, U, and Ba were the main contributors to the combined effects. Positive joint effects were observed between Cd and U on ALT, AST, GGT and ALP, and U and Ba had positive joint effects on ALT, AST and GGT. ConclusionExposures to Cd, U, and Ba were individually associated with multiple markers of liver injury. Mixed metal exposure might be adversely correlated with markers of liver function. The findings indicated the potential harmful effect of metal exposure on liver function.

A time- and space-resolved nuclear receptor atlas in mouse liver.

The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.

Biochemical Analysis of Liver Function in Individuals Affected and Unaffected by Dental Fluorosis in Endemic Fluoride Rural Areas of YSR Kadapa District, AP, India: A Cross-sectional Study

Introduction: Fluoride is known to affect the nervous system, kidneys, liver, and gastrointestinal system, in addition to teeth and bones, when consumed in amounts exceeding 1 ppm per day over a prolonged period. YSR Kadapa district has been identified as one of the districts with endemic fluoride areas in Andhra Pradesh, India, by the Central Groundwater Board of India. Aim: To assess the toxic effects of fluoride on liver function in individuals affected and unaffected by dental fluorosis, who consume high levels of fluoride in water, in the endemic fluoride rural areas of YSR Kadapa district. Materials and Methods: A cross-sectional study was conducted in six villages of YSR Kadapa district, where the drinking water has elevated fluoride content. A total of 320 subjects were selected as study participants. The subjects were divided into two groups based on age and dental fluorosis: Group A, aged between 21 and 40 years, and Group B, aged between 41 and 60 years. Subjects of each group were further sub-grouped according to presence or absence of fluorosis. The selected subjects were screened for dental fluorosis, and Groups A and B were further divided into subgroups based on the presence or absence of dental fluorosis. Blood samples were collected from the participants to assess liver function using serum levels of liver function markers such as total bilirubin (direct and indirect), Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), and Alkaline Phosphatase (ALP). Water and urine samples were also tested for fluoride levels using a fluoride ion meter. Statistical significance was determined using the t-test. Results: The mean fluoride levels in the water samples from the study areas ranged from 1.55±0.30 mg/L to 4.10±0.20 mg/L, and the urinary fluoride levels in the urine samples ranged from 0.54±0.46 mg/L to 2.13±0.845 mg/L. Among the study subjects, 60.6% (194) were affected by dental fluorosis, with 58.66% (88) belonging to Group A and 62.35% (106) belonging to Group B. There was no statistically significant difference in liver function markers in the serum between subjects with dental fluorosis and those without dental fluorosis in both groups (p>0.05), and the levels were within the normal reference range. Conclusion: This study found no impaired or altered liver function in adults affected by dental fluorosis and adults unaffected by dental fluorosis who consumed water with high levels of fluoride in the YSR Kadapa district.

Per- and perfluoroalkyl substances alternatives, mixtures and liver function in adults: A community-based population study in China

Experimental evidence has shown that per- and polyfluoroalkyl substances (PFAS) alternatives and mixtures may exert hepatotoxic effects in animals. However, epidemiological evidence is limited. This research aimed to explore associations of PFAS and the alternatives with liver function in a general adult population. The study participants consisted of 1,303 adults from a community-based cross-sectional investigation in Guangzhou, China, from November 2018 to August 2019. We selected 13 PFAS with detection rates > 85% in serum samples and focused on perfluorooctane-sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and their alternatives [6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), 8:2 Cl-PFESA, and perfluorohexanoic acid (PFHxA)] as predictors of outcome. Six liver function biomarkers (ALB, ALT, AST, GGT, ALP, and DBIL) were chosen as outcomes. We applied regression models with restricted cubic spline function to explore correlations between single PFAS and liver function and inspected the combined effect of PFAS mixtures on liver by applying Bayesian kernel machine regression (BKMR). We discovered positive associations among PFAS and liver function biomarkers except for ALP. For example, compared with the 25th percentile of PFAS concentration, the level of ALT increased by 12.36% (95% CI: 7.91%, 16.98%) for ln-6:2 Cl-PFESA, 5.59% (95% CI: 2.35%, 8.92%) for ln-8:2 Cl-PFESA, 3.56% (95% CI: −0.39%, 7.68%) for ln-PFHxA, 13.91% (95% CI: 8.93%, 19.13%) for ln-PFOA, and 14.25% (95% CI: 9.91%, 18.77%) for ln-PFOS at their 75th percentile. In addition, higher exposed serum PFAS was found to be correlated with greater odds of abnormal liver function. Analysis from BKMR models also showed an adverse association between PFAS mixtures and liver function. The combined effect of the PFAS mixture appeared to be non-interactive, in which PFOS was the main contributor to the overall effect. Our findings provide evidence of associations between PFAS alternatives, PFAS mixtures, and liver function in the general adult population.

Association Between Cadmium Exposure and Liver Function in Adults in the United States: A Cross-sectional Study.

ObjectivesCadmium is widely used, leading to extensive environmental and occupational exposure. Unlike other organs, for which the harmful and carcinogenic effects of cadmium have been established, the hepatotoxicity of cadmium remains unclear. Some studies detected correlations between cadmium exposure and hepatotoxicity, but others concluded that they were not associated. Thus, we investigated the relationship between cadmium and liver damage in the general population.MethodsIn total, 11 838 adult participants from National Health and Nutrition Examination Survey 1999-2015 were included. Urinary cadmium levels and the following liver function parameters were measured: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), total bilirubin (TB), and alkaline phosphatase (ALP). Linear and logistic regression analyses were performed to assess the associations between urinary cadmium concentrations and each liver function parameter after adjusting for age, sex, race/ethnicity, annual family income, smoking status, alcohol consumption status, physical activity, and body mass index.ResultsThe covariate-adjusted results of the linear regression analyses showed significant positive relationships between log-transformed urinary cadmium levels and each log-transformed liver function parameter, where beta±standard error of ALT, AST, GGT, TB, and ALP were 0.049±0.008 (p<0.001), 0.030±0.006 (p<0.001), 0.093±0.011 (p<0.001), 0.034±0.009 (p<0.001), and 0.040±0.005 (p<0.001), respectively. Logistic regression also revealed statistically significant results. The odds ratios (95% confidence intervals) of elevated ALT, AST, GGT, TB, and ALP per unit increase in log-transformed urinary cadmium concentration were 1.360 (1.210 to 1.528), 1.307 (1.149 to 1.486), 1.520 (1.357 to 1.704), 1.201 (1.003 to 1.438), and 1.568 (1.277 to 1.926), respectively.ConclusionsChronic exposure to cadmium showed positive associations with liver damage.

Examining Liver Function in Adults with Diabetes in the United States.

Hyperglycemia is the hallmark of various types of diabetes and considered to be a risk factor for several chronic disorders including liver function. Though liver is a dynamic organ, incessant glucotoxicity can lead to altered liver function. The goals of the present study were to examine the association between diabetes with liver functions amongst adults in the United States. We analyzed14,948 adultswith diabetes in the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2016.Diabetes and prediabetes were defined in accordance with theAmerican Diabetes Association 2021 guidelines. The association of demographic characteristics with glycemic levelswas analyzedusing the Chi-square test. A multivariate logistic regression model was constructed to evaluate the associations of glycemic levels with abnormal liver enzyme levels. Regression model was adjusted for age, sex, and ethnicity. The statistical analyses were performed using STATA ver. 14. A. p value of ≤0.05 or≤0.001 was considered statistically significant. A total of 14,948 adults (20 years and above) were included in this study. Sample mean age was 45.5±0.33 yrs., 54% were female, 53% were non-Hispanic White, and 60% had some college or graduate level education. In the overall sample, 19% adults were diabetic and 34% were pre-diabetic. Pre-diabetic glycemic levels were associated over one and half times higher odds of ALT (OR: 1.45, 95% CI: 1.31, 1.60, p<0.001) and over 1.3 times of higher odds AST (OR: 1.30, 95% CI: 1.14, 1.49,p<0.001). On the other hand, diabetic glycemic levels were associated with close to one and half times higher odds of ALT (OR: 1.37, 95% CI: 1.18, 1.59,p<0.001) and AST (OR: 1.48, 95% CI: 1.24, 1.76, p<0.001). On regression analysis, after adjustment, pre-diabetic and diabetic status was associated with high ALT (OR: 1.21, 95%CI: 1.11, 1.32, p<0.001), AST (OR: 1.14, 95%CI: 1.04, 1.27, p<0.05), ALP (OR: 1.40, 95%CI: 1.16, 1.68, p<0.001) and GGT (OR: 1.42, 95%CI: 1.24, 1.63, p<0.001). Our results indicated that diabetes is significantly associated with liver function. This observed association deserves further exploration to understand the longitudinal impact of diabetes on liver function.

STRATEGIES FOR HEPATOCYTE DIFFERENTIATION DERIVED FROM INDUCED PLURIPOTENT STEM CELLS USING SPHEROIDS

<h3>Background/Objective</h3> One of the main cells in the liver is the hepatocyte, which regulates the metabolism of various nutrients and xenobiotics, mediates endocrine function and excretion of toxic substances. Hepatocytes function in vitro have been studied for many years using primary hepatocytes and immortalized cells. Nevertheless, these cells show phenotypic instability or loss of adult liver functions and altered expression of important transcription factors. As an alternative to obtain a stable genetic background with preserved function and in large quantities, hepatocytes are being generated through differentiation of induced pluripotent stem cells (iPSC). However, one of the main problems to be overcome is the phenotype maturation. In this context, the objective of this work was to compare two different hepatocyte differentiation protocols using spheroids derived from iPSC. <h3>Methods</h3> Immunofluorescence for OCT3/4 and Nanog was performed to characterized pluripotent phenotype of iPSC and hepatocyte differentiation was induced for 28 days (D28). Two plating strategies were adopted to form the definitive endoderm: iPSC-monolayers (M) and iPSC-spheroids (S). To induce definitive endoderm, activin A and CHIR99021 were added to both plating conditions for 5 days. Prior hepatic maturation, iPSC-monolayers were also aggregated to form spheroids (MS). Subsequently, HGF and SB431542 were added to MS and S medium for 23 days. Spheroids were evaluated by real time PCR and immunofluorescence for hepatocyte-specific markers at D28. <h3>Results</h3> At protein level, the iPSC showed a pluripotent character through the nuclear presence of OCT3/4 and NANOG. At the end of the differentiation protocol, S differentiation strategy exhibited contractile cells. Albumin and cardiac troponin T were detected into the same spheroid by immunofluorescence. The MS strategy showed no beating cells. Also, CYP3A4 and albumin were detected by immunofluorescence and detectable mRNA levels were expressed for HNF4α, transferrin and alpha-1 antitrypsin. <h3>Conclusions</h3> Hepatocyte differentiation using spheroids requires a monolayer endoderm formation step in order to avoid the presence contractile cells at the end of protocol. Moreover, spheroid cells exhibited a great mature hepatocyte phenotype and can be used as a powerful tool for cell therapy, liver bioengineering, studies of drug efficacy and toxicity assays.

A review on biomarkers of bone metabolism in camels (Camelus dromedarius)

Bone metabolism biomarkers of bone formation and bone resorption are released during the bone remodeling processes. In humans as well as in veterinary medicine, these bone biomarkers have attracted much attention in the last decade. However, there are few reports found in the application of bone metabolism biomarkers in camel medicine. In camels, the most commonly used bone formation biomarkers include osteocalcin (OC) and bone-specific alkaline phosphatase (b-ALP). Concerning the bone resorption biomarkers, the most commonly used one is pyridinoline cross-links (PYD). OC is synthesised mostly from by mature osteoblasts. It is believed that OC is associated with mineralisation of newly formed osteoid. Therefore it is considered as a putative biomarker of bone formation and mineralisation. b-ALP is an isoform of alkaline phosphatase and plays an important role in bone formation. With normal liver function in adults, about 50% of total b-ALP is produced from bone in serum. The PYD cross-links, indicators of type I collagen resorption, are found in the mature collagen of bone. It is not only found in mature type I collagen, which is the major type of collagen in bone tissues, but also in collagen types II and III (Eyre et al, 1984). Increased concentrations of PYD in the blood or urine are most commonly considered as indicators of bone resorption. This review article was written to emphasise the importance of commonly used bone formation (OC and b-ALP) and bone resorption (PYD) biomarkers in camels. It is believed that research on bone formation and bone resorption biomarkers in camels will be increasingly used in the future in the diagnosis and prognosis of bone diseases.

Association of plasma antimony concentration with markers of liver function in Chinese adults

Environmental contextAntimony pollution has become a global issue given its wide distribution in the environment and its potential threat to human health. This large population-based study demonstrated that exposure to high levels of antimony may impair liver function in adults. The study highlights the potential hazard to liver function of antimony exposure, and provides convincing evidence of the need to monitor and control antimony exposure in the prevention of liver dysfunction. AbstractThe association of antimony exposure with serum liver enzymes and bilirubin levels remains unknown. We aimed to prospectively evaluate the associations of the plasma antimony concentration with serum liver enzymes [alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin [total (TBil), direct (DBil) and indirect bilirubin (IBil)] levels among the Chinese middle-aged and elderly population. A total of 4733 participants who were free of cardiovascular disease (CVD), cancer and chronic hepatitis at the baseline survey (2008–2010) of the Dongfeng-Tongji cohort were included in the current study. We measured the baseline plasma antimony concentration by inductively coupled plasma mass spectrometry (ICP-MS), and the serum liver enzymes and bilirubin levels at the resurvey visit (2013) by using an automatic analyser. In the fully adjusted generalised linear models, we observed that an increased plasma antimony concentration was significantly associated with higher bilirubin levels. Moreover, we found that plasma antimony was positively associated with the elevation of DBil (≥7.0μmolL−1), where the adjusted odds ratios (ORs) comparing the extreme tertiles was 1.35 (95% CI: 1.06, 1.70, P trend=0.01). Spline regression analyses indicated that the plasma antimony concentration was linearly associated with the elevation of TBil and DBil (overall P=0.004 and P=0.002 respectively). Our study suggested that exposure to high levels of antimony may impair liver function in adults. Further investigations are warranted to confirm these findings in other populations.

Association of Mercury Exposure with Decrease of Liver Function in Adults

Association of Mercury Exposure with Decrease of Liver Function in Adults

De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver.

The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis.

Mercury Exposure in Association With Decrease of Liver Function in Adults: A Longitudinal Study.

ObjectivesAlthough mercury (Hg) exposure is known to be neurotoxic in humans, its effects on liver function have been less often reported. The aim of this study was to investigate whether total Hg exposure in Korean adults was associated with elevated serum levels of the liver enzymes aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyltransferase (GGT).MethodsWe repeatedly examined the levels of total Hg and liver enzymes in the blood of 508 adults during 2010-2011 and 2014-2015. Cross-sectional associations between levels of blood Hg and liver enzymes were analyzed using a generalized linear model, and nonlinear relationships were analyzed using a generalized additive mixed model. Generalized estimating equations were applied to examine longitudinal associations, considering the correlations of individuals measured repeatedly.ResultsGGT increased by 11.0% (95% confidence interval [CI], 4.5 to 18.0%) in women and 8.1% (95% CI, -0.5 to 17.4%) in men per doubling of Hg levels, but AST and ALT were not significantly associated with Hg in either men or women. In women who drank more than 2 or 3 times per week, AST, ALT, and GGT levels increased by 10.6% (95% CI, 4.2 to 17.5%), 7.7% (95% CI, 1.1 to 14.7%), and 37.5% (95% CI,15.2 to 64.3%) per doubling of Hg levels, respectively, showing an interaction between blood Hg levels and drinking.ConclusionsHg exposure was associated with an elevated serum concentration of GGT. Especially in women who were frequent drinkers, AST, ALT, and GGT showed a significant increase, with a significant synergistic effect of Hg and alcohol consumption.

Small Maf deficiency recapitulates the liver phenotypes of Nrf1- and Nrf2-deficient mice.

Nrf1 and Nrf2 (NF-E2-related factors 1 and 2, respectively) are transcription factors that belong to the Cap'n'collar (CNC) family and play critical roles in various tissues, including the liver. Liver-specific Nrf1 knockout mice show hepatic steatosis, accompanied by dysregulation of various metabolic genes. Nrf2 knockout mice show impairment in the induction of antioxidant and xenobiotic-metabolizing enzyme genes. Although it has been shown that small Maf (sMaf) proteins act as obligatory partners of CNC proteins, their precise contributions to the function of CNC proteins remain unclear especially in the context of adult liver functions. To address this issue, we generated mice that conditionally lack expression of all sMaf proteins in the liver. The liver-specific sMaf-deficient mice develop hepatic steatosis and dysregulation of genes involved in lipid and amino acid metabolism and proteasomal subunit expression. Importantly, the gene expression profiles in the sMaf-deficient livers share a strong similarity with those in Nrf1-deficient livers. In addition, the basal expression levels of a number of Nrf2 target genes were diminished in the sMaf-deficient livers. These results provide the first genetic evidence that sMaf proteins are indispensable for liver functions as heterodimeric partners for Nrf1 and Nrf2.

Effect of exercise training on liver function in adults who are overweight or exhibit fatty liver disease: a systematic review and meta-analysis

ObjectiveExercise training has been shown to have beneficial effects on liver function in adults overweight or with fatty liver disease. To establish which exercise programme characteristics were likely to elicit...

Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells.

Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults.

Noninvasive assessment of liver function in adults with congenital heart disease (ACHD) by transient elastography (Fibroscan), Acoustic Radiation Force Impulse Imaging (ARFI) and biochemical markers

Objectives: To assess the impact of ultrasound based procedures (USBP) and specific biochemical fibrosis markers (BFM) on noninvasive staging of liver fibrosis/cirrhosis (LF/LC) in ACHD.

In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells.

Alcohol consumption has long been associated with a majority of liver diseases and has been found to influence both fetal and adult liver functions. In spite of being one of the major causes of morbidity and mortality in the world, currently, there are no effective strategies that can prevent or treat alcoholic liver disease (ALD), due to a lack of human-relevant research models. Recent success in generation of functionally active mature hepatocyte-like cells from human-induced pluripotent cells (iPSCs) enables us to better understand the effects of alcohol on liver functions. Here, we describe the method and effect of alcohol exposure on multistage hepatic cell types derived from human iPSCs, in an attempt to recapitulate the early stages of liver tissue injury associated with ALD. We exposed different stages of iPSC-induced hepatic cells to ethanol at a pathophysiological concentration. In addition to stage-specific molecular markers, we measured several key cellular parameters of hepatocyte injury, including apoptosis, proliferation, and lipid accumulation.