Hepatic Storage Research Articles

Liver Fibrosis Is Enhanced by a Higher Egg Burden in Younger Mice Infected with S. mansoni.

Schistosomiasis affects over 250 million people worldwide, with the highest prevalence at the age of 10-14 years. The influence of the host's age on the severity of liver damage is unclear. We infected male 8, 14, and 20-week-old mice with S. mansoni. Hepatic damage, inflammation, fibrosis, and metabolism were analyzed by RT-qPCR, Western blotting, ELISA, immunohistochemistry, and mechanistic transwell chamber experiments using S. mansoni eggs and human hepatic stellate cells (HSCs) or primary mouse hepatocytes. Major results were validated in human biopsies. We found that hepatosplenomegaly, granuloma size, egg load, inflammation, fibrosis, and glycogen stores all improved with the increasing age of the host. However, serum alanine transaminase (ALT) levels were lowest in young mice infected with S. mansoni. Hepatic carbohydrate exploitation was characterized by a shift towards Warburg-like glycolysis in S. mansoni-infected animals. Notably, S. mansoni eggs stimulated hepatic stellate cells to an alternatively activated phenotype (GFAP+/desmin+/αSMA-) that secretes IL-6 and MCP-1. The reduction of fibrosis in older age likely depends on the fine-tuning of regulatory and inflammatory cytokines, alternative HSC activation, and the age-dependent preservation of hepatic energy stores. The current results emphasize the significance of investigations on the clinical relevance of host age-dependent liver damage in patients with schistosomiasis.

Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting

Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.

LXR Agonist T0901317's Hepatic Impact Overrules Its Atheroprotective Action in Macrophages, Driving Early Atherogenesis in Chow-Diet-Fed Male Apolipoprotein E Knockout Mice.

Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR.

Thioredoxin domain containing 5 is involved in the hepatic storage of squalene into lipid droplets in a sex-specific way

Hepatic thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family found associated with anti-steatotic properties of squalene and located in the endoplasmic reticulum and in lipid droplets. Considering that the latter are involved in hepatic squalene accumulation, the present research was aimed to investigate the role of TXNDC5 on hepatic squalene management in mice and in the AML12 hepatic cell line. Wild-type and TXNDC5-deficient (KO) mice were fed Western diets with or without 1% squalene supplementation for 6 weeks. In males, but not in females, absence of TXNDC5 blocked hepatic, but not duodenal, squalene accumulation. Hepatic lipid droplets were isolated and characterized using label-free LC-MS/MS analysis. TXNDC5 accumulated in this subcellular compartment of mice receiving squalene and was absent in TXNDC5-KO male mice. The latter mice were unable to store squalene in lipid droplets. CALR and APMAP were some of the proteins that responded to the squalene administration in all studied conditions. CALR and APMAP were positively associated with lipid droplets in the presence of squalene and they were decreased by the absence of TXNDC5. The increased squalene content was reproduced in vitro using AML12 cells incubated with squalene-loaded nanoparticles and this effect was not observed in an engineered cell line lacking TXNDC5. The phenomenon was also present when incubated in the presence of a squalene epoxidase inhibitor, suggesting a mechanism of squalene exocytosis involving CALR and APMAP. In conclusion, squalene accumulation in hepatic lipid droplets is sex-dependent on TXNDC5 that blocks its secretion.

Increased expression or activation of TRPML1 reduces hepatic storage of toxic Z alpha-1 antitrypsin

Mutant Z alpha-1 antitrypsin (ATZ) accumulates in globules in the liver and is the prototype of proteotoxic hepatic disease. Therapeutic strategies aiming at clearance of polymeric ATZare needed. Transient receptor potential mucolipin-1 (TRPML1) is a lysosomal Ca2+ channel that maintains lysosomal homeostasis. In this study, we show that by increasing lysosomal exocytosis, TRPML1 gene transfer or small-molecule-mediated activation of TRPML1 reduces hepatic ATZ globules and fibrosis in PiZ transgenic mice that express the human ATZ. ATZ globule clearance induced by TRPML1 occurred without increase in autophagy or nuclear translocation of TFEB. Our results show that targeting TRPML1 and lysosomal exocytosis is a novel approach for treatment of the liver disease due to ATZ and potentially other diseases due to proteotoxic liver storage.

Visco-Elastic Parameters at Three-Dimensional MR Elastography for Diagnosing Non-Alcoholic Steatohepatitis and Substantial Fibrosis in Mice.

Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is a growing cause of liver cirrhosis and cancer. The performance of the magnetic resonance elastography (MRE) visco-elastic parameters in diagnosing progressive forms of NAFLD, including nonalcoholic steatohepatitis (NASH) and substantial fibrosis (F ≥ 2), needs to be clarified. To assess the value of three-dimensional MRE visco-elastic parameters as markers of NASH and substantial fibrosis in mice with NAFLD. Prospective. Two mouse models of NAFLD were induced by feeding with high fat diet or high fat, choline-deficient, amino acid-defined diet. 7T/multi-slice multi-echo spin-echo MRE at 400 Hz with motion encoding in the three spatial directions. Hepatic storage and loss moduli were calculated. Histological analysis was based on the NASH Clinical Research Network criteria. Mann-Whitney, Kruskal-Wallis tests, Spearman rank correlations and multiple regressions were used. Diagnostic performance was assessed with areas under the receiver operating characteristic curves (AUCs). P value <0.05 was considered significant. Among the 59 mice with NAFLD, 21 had NASH and 20 had substantial fibrosis (including 8 mice without and 12 mice with NASH). The storage and loss moduli had similar moderate accuracy for diagnosing NASH with AUCs of 0.67 and 0.66, respectively. For diagnosing substantial fibrosis, the AUC of the storage modulus was 0.73 and the AUC of the loss modulus was 0.81, indicating good diagnostic performance. Using Spearman correlations, histological fibrosis, inflammation and steatosis, but not ballooning, were significantly correlated with the visco-elastic parameters. Using multiple regression, fibrosis was the only histological feature independently associated with the visco-elastic parameters. MRE in mice with NAFLD suggests that the storage and loss moduli have good diagnostic performance for detecting progressive NAFLD defined as substantial fibrosis rather than NASH. 1 TECHNICAL EFFICACY STAGE: 2.

Fetal factors disrupt placental and maternal iron homeostasis in murine β-thalassemia

AbstractPregnancy rates in β-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively affect their unborn offspring. The experimental design included these groups: wild-type (WT) dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, nonpregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all 3 groups of experimental dams. Intestinal 59Fe absorption was lower in Th3/+ dams (as compared with WT1/2 dams) but splenic 59Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction, and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when mothers with thalassemia have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress likely contributed to fetal growth impairment; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental ferroportin expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.

High prevalence of vitamin B-12 deficiency before and early after gastrectomy in patients with gastric cancer.

Gastrectomy causes vitamin B-12 deficiency since vitamin B-12 requires gastric acid and intrinsic factor for its absorption. Vitamin B-12 deficiency is considered to develop years after gastrectomy because of large hepatic storage. However, most gastric cancer develops after long-standing atrophic gastritis with vitamin B-12 malabsorption. We have investigated vita-min B-12 status in 22 patients before gastrectomy and 53 patients after gastrectomy due to gastric cancer, also with consideration on post-gastrectomy anemia. Blood vitamin B-12, folic acid, homocysteine concentrations, parameters of anemia, and dietary intake were evaluated. Percentage of patients with severe vitamin B-12 deficiency (serum vitamin B-12 < 150 pmol/L), vitamin B-12 deficiency (150 pmol/L to < 258 pmol/L) was 19.0 %, and 52.4 % respectively in patients gastrectomized within three years. Before gastrectomy, three and seven patients exhibited severe deficiency and deficiency, respectively. In gastrectomized patients, plasma homocysteine concentration was inversely associated with serum vitamin B-12 concentration, and vitamin B-12 deficiency- and iron deficiency- anemia coexisted with their mean corpuscular volume within the reference range. Vitamin B-12 deficiency is prevalent in patients early after and before gastrectomy. Coexistence of vitamin B-12 and iron deficiency obscures the diagnosis of post-gastrectomy anemia, and necessitates the blood vitamin B-12 measurement.

Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period

In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m2/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.

Effect of Methotrexate on Liver in Patient with Rheumatoid Arthritis

Background: Methotrexate helps your immune system from assaulting your body's cells by calming it down. This helps to lessen the inflammation that causes rheumatoid arthritis's swollen and stiff joints, psoriasis' thickened skin, and Crohn's disease's gut damage. Because of its powerful effectiveness and safety, In the treatment of rheumatoid arthritis, methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drug (DMARD) (RA).Although MTX aids a huge percentage of RA patients, it is not without adverse effects. When treating rheumatoid arthritis patients with the MTX, wide a variety of adverse effects, from minor to severe, can occur, leading to therapy termination. One putative harmful effect of methotrexate on the due to a local folate deficiency, there is a reduction in hepatic folate stores and toxicity. When MTX used with other medications, further research is needed to improve efficacy while reducing adverse effects. The management of MTX therapy is also reviewed, as well as options for dealing with adverse effects that may arise. Objective: The purpose of this study was to see how methotrexate affected individuals after 6 to 12 months of treatment for rheumatoid arthritis. Methods: Data was collected at the Shalamar hospital, Pakistan, between January 2021 and June 2022. Non-Probability Purposive Sample is the sampling strategy used in this investigation. Following the assignment of a study subject, the research took around 6 months to complete. After giving their informed consent, 120 patients between the ages of 30 and 50 were involved in this study. Data will be acquired using data collection technologies when an informed written permission form has been completed. Result: In this study 120 Rheumatoid Arthritis patients were studied, with 64 males (53.3%) and 56 women (46.7%) having an average age of 40 to 45 years and a range of 30 to 50 years. took part in the study, as shown in the graph (Table 3). In this study, 4 patients are 30 to 35 years old and have a percentage of (3.3%), 18 patients are 36 to 40 years old and have a percentage of (15%), another age group is 41 to 45 years old and has a percentage of (47.5%), and the last age group is 46 to 50 years old and has a percentage of (34.2%), as shown in the table (Table 2). The (Table 5) indicates the usual range of LFTs before Methotrexate, which is completely normal with no fluctuation in LFT parameters. As demonstrated in (Tables 6 and 8) where we examine the before and after effects of Methotrexate on the basis of patient immunity in 79 patients, the values of LFTs alter and become higher in comparison to normal, with a percentage of (65.8%). We compare the impact of Methotrexate on the basis of Gender using cross tabulation, which shows that LFTs were high in 41 males (67.1%) and 38 females (64.9%), as indicated in (Table 10). Finally, we compare the effect of Methotrexate on the basis of age factor as shown in (Table 11). After MTX therapy, RA patients experienced gastrointestinal side effects such as nausea, vomiting, and diarrhea, implying that MTX therapy will definitely affect the LFTs level and, most likely, according to the current study, will raise the LFTs level in blood, which will be treated promptly before further serious complications arise. A timely follow-up will be advised to all patients with consistently high LFTs levels. Conclusion: In this study, we discussed rheumatoid arthritis and the effects of methotrexate on rheumatoid arthritis patients' lives. It would appear that methotrexate is gaining popularity in the treatment of rheumatoid arthritis. Although there is risk of infection &amp; probable cancer, the hazards are much outweighed by the potential therapeutic benefits. We also talked about R.A. diagnostic procedures. We covered the many characteristics of this autoimmune condition as well as several diagnostic approaches in this study.

193-OR: Chronotherapy with the Glucokinase Activator AZD1656 Greatly Affects Its Ability to Improve Metabolism in Obese Zucker Rats

Circadian rhythms play critical roles in regulating metabolism, including daily feeding/fasting periods and oscillating expressions of certain genes. Glucokinase (Gck) , expressed in the liver and pancreas, is central for whole-body glucose homeostasis by acting as a glucose sensor and regulating metabolism according to prevailing glucose levels. Gck expression has also been shown to follow a circadian rhythm. Gck activators (GKAs) effectively reduce hyperglycemia, however, adverse events have also involved hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of Gck, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. We compared the metabolic effects following differentially timed administrations of the GKA AZD1656 in the obese, insulin resistant Zucker rat. Four weeks of continuous treatment significantly improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, a robust reduction in hepatic steatosis and inflammation on top of improved glycemia, was observed when AZD1656 administration was timed to feeding periods only. When AZD1656 was timed to fasting periods, detrimental metabolic effects were observed, including impaired glycemic control, severe liver steatosis and elevated inflammation. Mechanistically, timing AZD1656 administration to feeding periods was found to divert de novo lipogenesis-derived lipids away from hepatic storage towards VLDL synthesis and secretion, without affecting plasma triglyceride levels. In conclusion, intermittent AZD1656 dosing timed to feeding periods promotes glucose disposal when needed the most, while the daily drug holiday allows for maintained metabolic flexibility and avoids hepatic steatosis. Chronotherapeutic approaches should be considered for the development of GKAs and other drugs acting on metabolic targets. Disclosure T. Kroon: Employee; AstraZeneca. I. Alexandersson: Employee; AstraZeneca. A. Ferm: Employee; AstraZeneca. M. Petersson: Employee; AstraZeneca. S. Maurer: Employee; AstraZeneca, Merck Sharp &amp; Dohme Corp. B. Zarrouki: Employee; AstraZeneca. K. Wallenius: Employee; AstraZeneca. N.D. Oakes: Employee; AstraZeneca. J. Boucher: Employee; AstraZeneca, Evotec International GmbH.

Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes.

Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.

Genetic dissection in mice reveals a dynamic crosstalk between the delivery pathways of vitamin A

Vitamin A is distributed within the body to support chromophore synthesis in the eyes and retinoid signaling in most other tissues. Two pathways exist for the delivery of vitamin A: the extrinsic pathway transports dietary vitamin A in lipoproteins from intestinal enterocytes to tissues, while the intrinsic pathway distributes vitamin A from hepatic stores bound to serum retinol binding protein (RBP). Previously, the intestine-specific homeodomain transcription factor (ISX) and the RBP receptor STRA6 were identified as gatekeepers of these pathways; however, it is not clear how mutations in the corresponding genes affect retinoid homeostasis. Here, we used a genetic dissection approach in mice to examine the contributions of these proteins in select tissues. We observed that ISX deficiency increased utilization of both preformed and provitamin A. We found that increased storage of retinoids in peripheral tissues of ISX-deficient mice was dependent on STRA6 and induced by retinoid signaling. In addition, double-mutant mice exhibited a partial rescue of the Stra6 mutant ocular phenotype. This rescue came at the expense of a massive accumulation of vitamin A in other tissues, demonstrating that vitamin A is randomly distributed when present in excessive amounts. Remarkably, provitamin A supplementation of mutant mice induced the expression of the RBP receptor 2 in the liver and was accompanied by increased hepatic retinyl ester stores. Taken together, these findings indicate dynamic crosstalk between the delivery pathways for this essential nutrient and suggest that hepatic reuptake of vitamin A takes place when excessive amounts circulate in the blood.

226 Evaluation of a Low-Moisture, Molasses-Based Block Containing Organic Trace Minerals and a Saccharomyces Cerevisiae Fermentation Culture in Newly Weaned Beef Steer Calves

Abstract The objective of this study was to evaluate growth performance responses and hepatic trace mineral status of newly weaned steer calves offered a molasses-based “stress” tub. Steers [n = 46; body weight (BW) = 240; SEM = 1.0 kg) were used in a randomized complete block design experiment. On d -1 all steers were stratified by initial BW and allotted to pens (n = 4 to 5 steers per pen; 5 pens/treatment).Treatments were: 1) No “stress” tub (Con) or 2) Ad libitum access to a “stress” tub (Stress Tub; Purina Animal Nutrition, St. Louis, MO) for the first 21-d (Tub). Steers were allotted to their study pens within 36-h of weaning and the “stress” tub was introduced approximately 24-h post arrival. Tub disappearance was monitored daily. Liver biopsies (n = 2 steers/pen) were collected on d 7, 21, and 42 for determination of Co, Cu, Mn, and Zn. From d 1 to 21 and d 1 to 42 steers from in the Tub treatment consumed greater (P ≤ 0.01) amounts of Co, Cu, Mn, and Zn. A treatment × day interaction for hepatic concentrations of Co (P = 0.09), Cu (P = 0.01), and Zn (P = 0.01) were noted. On d 7, steers from Tub had greater (P≤0.01) hepatic Co, Cu, and Zn . On d 21, steers from Tub had greater (P ≤ 0.01) hepatic Co and Cu. On d 42 steers from Tub had greater (P = 0.01) hepatic concentrations of Cu. During the initial 21-d of the experiment gain efficiency was enhanced (P = 0.03) by 25.0% in steers from Tub compared with Con. Cumulative ADG, DMI, dietary NE utilization, and G:F did not differ (P ≥ 0.14). It is concluded that stress tubs do not influence overall growth performance or NE value of the diet during a 42-d period. Stress tub consumption increased hepatic mineral stores during the initial 21-d and enhanced Cu status of calves throughout the 42-d receiving period.

Vitamin Supplements as a Nutritional Strategy against Chronic Alcohol Consumption? An Updated Review.

Several studies have shown that blood vitamin levels are low in alcoholic patients. In effect, alcohol use abuse is considered a chronic disease that promotes the pathogenesis of many fatal diseases, such as cancer and liver cirrhosis. The alcohol effects in the liver can be prevented by antioxidant mechanisms, which induces enzymatic as well as other nonenzymatic pathways. The effectiveness of several antioxidants has been evaluated. However, these studies have been accompanied by uncertainty as mixed results were reported. Thus, the aim of the present review article was to examine the current knowledge on vitamin deficiency and its role in chronic liver disease. Our review found that deficiencies in nutritional vitamins could develop rapidly during chronic liver disease due to diminished hepatic storage and that inadequate vitamins intake and alcohol consumption may interact to deplete vitamin levels. Numerous studies have described that vitamin supplementation could reduce hepatotoxicity. However, further studies with reference to the changes in vitamin status and the nutritional management of chronic liver disease are in demand.

Qualitative and Quantitative Changes in Total Lipid Concentration and Lipid Fractions in Liver Tissue of Periparturient German Holstein Dairy Cows of Two Age Groups.

Fatty liver syndrome (FLS) is a common disease in high-producing dairy cows. Studies in humans suggest that the different hepatic lipid fractions play a role in this context. In dairy cows, little is known about the composition of fat stored in the liver, its periparturient dynamics, and the effect of cows' age. Therefore, our goal was to generate primary data in healthy cows to serve as reference values for future studies. Eight healthy German Holstein cows (2nd lactation, n = 3; ≥3rd lactation, n = 5) were examined 14 d antepartum and 7, 28, and 42 d postpartum. The examinations included clinical assessment, liver biopsy, blood sampling, and recording of milk yield. Total lipids (TL) in liver tissue were measured gravimetrically. The TL were separated into lipid fractions (triacylglycerol, TAG; phospholipids, PL; non-esterified fatty acids, NEFA; and cholesterol esters) using thin-layer chromatography, followed by gas chromatography for fatty acid determination. Concentrations of NEFA, ß-hydroxybutyrate, and cholesterol were analyzed in blood. Concentrations of TL, TAG, NEFA, and cholesterol esters in liver tissue and NEFA in blood increased in the periparturient period. The older cows had higher hepatic TL, TAG, and PL concentrations, higher relative hepatic concentrations of TAG in TL, higher NEFA concentrations in blood, a greater decrease in body condition, and higher milk yields between d 9 and 40 than the younger cows. We proposed that due to higher milk yield, older cows mobilized and deposited more fat in the liver, and the increase in hepatic TAG concentration was longer-lasting than in younger cows. Higher levels of structural lipids (PL) in older cows could be explained by higher demand for storage of TAG and cholesterol esters in lipid droplets or for the export of TAG via very-low-density lipoproteins. Results show that hepatic fat storage is a reversible process and does not necessarily cause clinical disease. Nevertheless, older cows have a more sustained and greater increase in hepatic TAG concentration, which may explain their increased risk of FLS. The results are limited in their extrapolation due to the small sample size and thereby possible selection bias but present a valuable basis for future studies.

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

A farewell to phlebotomy\u2014use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report

BackgroundHuman hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis.Case presentationA 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue.ConclusionThe discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.

Hemosiderin Accumulation in Liver Decreases Iron Availability in Tachycardia-Induced Porcine Congestive Heart Failure Model.

Despite advances in the management of iron deficiency in heart failure (HF), the mechanisms underlying the effects of treatment remain to be established. Iron distribution and metabolism in HF pathogenesis need to be clarified. We used a porcine tachycardia-induced cardiomyopathy model to find out how HF development influences hepatic and myocardial iron storing, focusing on ferritin, the main iron storage protein. We found that cumulative liver congestion (due to the decrease of heart function) overwhelms its capacity to recycle iron from erythrocytes. As a consequence, iron is trapped in the liver as poorly mobilized hemosiderin. What is more, the ferritin-bound Fe3+ (reflecting bioavailable iron stores), and assembled ferritin (reflecting ability to store iron) are decreased in HF progression in the liver. We demonstrate that while HF pigs show iron deficiency indices, erythropoiesis is enhanced. Renin–angiotensin–aldosterone system activation and hepatic hepcidin suppression might indicate stress erythropoiesisinduced in HF. Furthermore, assembled ferritin increases but ferritin-bound Fe3+ is reduced in myocardium, indicating that a failing heart increases the iron storage reserve but iron deficiency leads to a drop in myocardial iron stores. Together, HF in pigs leads to down-regulated iron bioavailability and reduced hepatic iron storage making iron unavailable for systemic/cardiac needs.

Protein Misfolding and Aggregation: The Relatedness between Parkinson's Disease and Hepatic Endoplasmic Reticulum Storage Disorders.

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson’s disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.