Size Of Hepatocytes Research Articles

Effects of Artificial Sweeteners Aspartame and Sucralose on the Size of Hepatocytes in Rat Liver

Background: The use of artificial sweeteners in excess these days to lose weight and to remain fit without knowing its effects on our health, gave me a thought to conduct this study to see whether they are safe or not for liver health. Objectives: The objectives of this study were to see the effects of Aspartame and Sucralose (Artificial sweeteners) on rat hepatocytes and also to compare their effects to choose relatively safe artificial sweetener for routine use. Method: 50 adult Wistar albino rats were used in this study. Animals were divided into five groups by random lottery method. Control group I animals were given distilled water by oral gavage. The group II and III animals were given 40mg and 1000mg/kg body weight of Aspartame respectively. Whereas animals of group IV and V were given 5mg and 1000mg/kg body weight of Sucralose respectively. Doses to experimental animals were given by oral gavage once daily for a total duration of eight weeks. At the end of the experiment rats were sacrificed, livers were dissected out and after specimen preservation the tissue was passed through stages of slide preparation and later H and E staining was performed. Results: Light microscopic examination of liver slides revealed that largest sizes of hepatocytes were observed in high dose groups of Aspartame and Sucralose. Conclusion: The increase in the size of hepatocytes was observed in high dose groups of Aspartame and Sucralose whereas changes seen in low dose groups were not significant. Keywords: Artificial sweeteners, Histology of rat liver, Size of hepatocytes.

Cynara Scolymus (Artichoke) Improves Liver Regeneration after Partial Liver Resection in Rats

Objective: Liver regeneration is necessary to restore hepatic mass and functional capacity after partial hepatectomy (PH). Cynara scolymus (CS) is a pharmacologically important plant that contains phenolic acids and flavonoids, and experimental studies have indicated that it has antioxidant and hepatoprotective effects. The aim of this study was to investigate the role of CS in liver regeneration after PH in rats. 
 Methods: A total of 36 Wistar albino rats weighing 280.5 ± 18.6 g were used. CS leaf extract was administered after partial hepatectomy. The rats were sacrificed at postoperative day 14, and the histological changes were assessed. The mitotic index (MI), nucleus size, hepatocyte size, and binucleation rate (BR) of hepatocytes were assessed using hematoxylin-eosin (H&E) staining. 
 Results: The rats that received CS extract had significant differences in liver regeneration markers, including the hepatocyte size, mitotic index, and Ki-67 proliferation index (p

Effects of Artificial Sweeteners Aspartame and Sucralose on the Size of Hepatocytes in Rat Liver

Background: The excessive use of artificial sweeteners now a days just to lose weight and to remain fit and due to other reasons without knowing its effects on liver gave me a thought to conduct this study to see whether they are safe or not for liver health. Aim: To see the effects of artificial sweeteners Aspartame and Sucralose on the size of rat hepatocytes and to compare their effects to choose relatively safe artificial sweetener for routine use. Methods: Fifty adult Wistar albino rats used in this study were randomly divided into five groups. Group I (control group) animals were given drinking water by oral gavage. The animals of group II and III were given low (40mg/kg body weight) and high doses (1000mg/kg body weight) of Aspartame respectively. Similarly, animals of group IV and V were given low (5mg/kg body weight) and high doses (1000mg/kg body weight) of Sucralose respectively. Doses were given by oral gavage once daily, six days a week for a total duration of eight weeks. At the end of the experiment histological observation of liver in all animal groups was made. Results: Microscopic examination revealed that hepatocytes of group III animals (high dose group of Aspartame) had largest size with the mean value of 20.86±2.00µm as compared to the control group hepatocytes having mean value of 16.46±1.74µm. Conclusion: The increase in the size of hepatocytes was seen in high dose groups of Aspartame and Sucralose whereas changes seen in low dose groups of Aspartame and Sucralose were not significant. Keywords: Artificial sweeteners, Histology of rat liver, Size of hepatocytes.

The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver.

Every type of cell in an animal maintains a specific size, which likely contributes to its ability to perform its physiological functions. While some cell size control mechanisms are beginning to be elucidated through studies of cultured cells, it is unclear if and how such mechanisms control cell size in an animal. For example, it was recently shown that RB, the retinoblastoma protein, was diluted by cell growth in G1 to promote size-dependence of the G1/S transition. However, it remains unclear to what extent the RB-dilution mechanism controls cell size in an animal. We therefore examined the contribution of RB-dilution to cell size control in the mouse liver. Consistent with the RB-dilution model, genetic perturbations decreasing RB protein concentrations through inducible shRNA expression or through liver-specific Rb1 knockout reduced hepatocyte size, while perturbations increasing RB protein concentrations in an Fah −/− mouse model increased hepatocyte size. Moreover, RB concentration reflects cell size in G1 as it is lower in larger G1 hepatocytes. In contrast, concentrations of the cell cycle activators Cyclin D1 and E2f1 were relatively constant. Lastly, loss of Rb1 weakened cell size control, i.e., reduced the inverse correlation between how much cells grew in G1 and how large they were at birth. Taken together, our results show that an RB-dilution mechanism contributes to cell size control in the mouse liver by linking cell growth to the G1/S transition.

Spatiotemporal expression of HMGB2 regulates cell proliferation and hepatocyte size during liver regeneration

Liver regeneration is an extraordinarily complex process involving a variety of factors; however, the role of chromatin protein in hepatocyte proliferation is largely unknown. In this study, we investigated the functional role of high-mobility group box 2 (HMGB2), a chromatin protein in liver regeneration using wild-type and HMGB2-knockout (KO) mice. Liver tissues were sampled after 70% partial hepatectomy (PHx), and analyzed by immunohistochemistry, western blotting and flow cytometry using various markers of cell proliferation. In WT mice, hepatocyte proliferation was strongly correlated with the spatiotemporal expression of HMGB2; however, cell proliferation was significantly delayed in hepatocytes of HMGB2-KO mice. Quantitative PCR demonstrated that cyclin D1 and cyclin B1 mRNAs were significantly decreased in HMGB2-KO mice livers. Interestingly, hepatocyte size was significantly larger in HMGB2-KO mice at 36–72 h after PHx, and these results suggest that hepatocyte hypertrophy appeared in parallel with delayed cell proliferation. In vitro experiments demonstrated that cell proliferation was significantly decreased in HMGB2-KO cells. A significant delay in cell proliferation was also found in HMGB2-siRNA transfected cells. In summary, spatiotemporal expression of HMGB2 is important for regulation of hepatocyte proliferation and cell size during liver regeneration.

EFFECTS OF AVOCADO (PERSEA AMERICANA) AQUEOUS SEED EXTRACT ON GROSS FEATURES OF LIVER AND HEPATOCYTE SIZE IN ISONIAZID AFFECTED ALBINO RATS

Background: Isoniazid (INH) has been associated with severe hepatotoxicity and fatal liver injury. This study aimed to observe the hepatoprotective effects of concomitant use of avocado aqueous seed extract on the gross features of liver and size of hepatocytes in INH induced hepatotoxicity in albino rats. Methods: This experimental study was conducted from Jan–Jun 2019. Thirty-six male albino rats were divided into 4 groups. Groups were administered treatment orally for 30 days. Group 1 received distilled water 1 ml/Kg/day. Group 2 received INH 100 mg/Kg/day dissolved in 1 ml distilled water. Group 3 was given aqueous avocado seed extract 250 mg/Kg/day in 2 ml distilled water and Group 4 received aqueous avocado seed extract 500 mg/Kg/day in 4 ml distilled water. Results: Highest mean liver weight was seen in Group 4 and lowest in Group 2. The weight of liver was significantly different among all groups but Relative Tissue Weight Index among all groups was insignificant. Colour of liver in four groups varied from reddish to pale red and reddish brown. The texture of all livers was smooth. Hepatocyte size was found to be largest in Group 2 and smallest in Group 1. Comparison among groups showed significant difference in sizes of hepatocytes. Conclusion: Concomitant use of aqueous avocado seed extract prevents INH-induced hepatotoxicity by maintaining body and liver weights, gross features of liver, and size of hepatocytes in a dose-dependent manner. Pak J Physiol 2022;18(2):38–42

Influence of constant lightning on liver health: an experimental study.

Light pollution has become a serious problem in many urbanized areas of the world. The impact of prolonged exposure to light and consequent disruption of natural circadian rhythms has significant health implications. The current study was undertaken to evaluate the effect of prolonged exposure to light, simulating urban light pollution, on liver health. In order to evaluate the effect of prolonged exposure to light, we examined the morphofunctional state, immunohistochemical and micromorphometric parameters of rat liver in normal conditions and following prolonged lighting exposure. Our results show that nocturnal light disruption triggers a cell death in the liver within 3weeks (necrosis and apoptosis of hepatocytes) and stimulates a change in normal cellular karyometric parameters. At the same time, intracellular regeneration takes place within the organ, which manifests through hepatocyte hypertrophy. Under the influence of constant illumination, the circadian rhythms (CRs) of the size of hepatocytes and their nuclei are restructured, and the rhythm of the nuclear-cytoplasmic ratio is destroyed. The destruction of the CR of expression of p53 and Ki-67 also occurs against the background of the rearrangement of the daily rhythmicity of Per2 and Bmal1. The revealed changes in the morphofunctional state of the liver under the influence of light pollution indicate that a violation of normal illumination regimes is a potent factor leading to significant structural changes in the liver.

Fenofibrate induced‐hepatomegaly and liver regeneration is PPARα dependent and partially related to the activation of YAP pathway

Background and ObjectiveFenofibrate, an agonist of peroxisome proliferator activated receptor α (PPARα), has been widely used as a lipid‐regulating agent in clinical practice. Recent studies found that fenofibrate can significantly induce hepatomegaly in mice, but the involved mechanisms remain unclear.MethodsThe effect of fenofibrate on hepatomegaly and liver regeneration was investigated in several strains of genetically‐modified mice including Pparafl/fland PparaΔHep mice. Staining assays were performed to investigate the effect of fenofibrate on hepatocyte size and proliferation during hepatomegaly and liver regeneration. AAV‐Yap shRNA mice model was further used to determine the role of YAP in PPARα‐induced hepatomegaly. Western blot analysis was used to detect the protein expressions of YAP signaling pathway as well as other factors potentially involved in fenofibrate‐induced hepatomegaly.ResultsThe study demonstrated that fenofibrate significantly induced liver enlargement in wild‐type and Pparafl/fl mice, while this effect was abolished in hepatocyte‐specific Ppara‐deficient (PparaΔHep) mice. Furthermore, fenofibrate significantly promoted liver regeneration in wild‐type mice following 70% partial hepatectomy (PHx). Staining assays revealed that fenofibrate promoted hepatocyte enlargement around the central vein area and hepatocyte proliferation around the portal vein area in wild‐type, Pparafl/fl and PHx mice. Fenofibrate regulated protein expressions of YAP and its downstream targets (CTGF, CRY61 and ANKRD1) as well as proliferation‐related proteins (CCNA1, CCND1 and CCNE1). Suppression of YAP using AAV‐Yap shRNA repressed fenofibrate‐induced hepatomegaly, as well as hepatocyte enlargement and proliferation. Other factors might also participate in fenofibrate‐induced hepatomegaly, including MYC, KRT23, RHOA and RAS.ConclusionThese studies revealed a novel role of fenofibrate in promoting liver enlargement and regeneration, which is PPARα dependent and partially related to the activation of YAP signaling pathway. These findings provide clinical relevance of fenofibrate as a potential medication for promoting liver regeneration.

Chronic exposure to high-density polyethylene microplastic through feeding alters the nutrient metabolism of juvenile yellow perch (Perca flavescens).

Microplastics are emergent contaminants threatening aquatic organisms including aquacultured fish. This study investigated the effects of high-density polyethylene (HDPE, 100 to 125 μm) on yellow perch (Perca flavescens) based on integrative evaluation including growth performance, nutritional status, nutrient metabolism, fish health, and gut microbial community. Five test diets (0, 1, 2, 4, or 8 g HDPE/100 g diet) containing 41% protein and 10.5% lipid were fed to juvenile perch (average body weight, 25.9 ± 0.2 g; n = 15) at a feeding rate of 1.5% to 2.0% body weight daily. The feeding trial was conducted in a flow-through water system for 9 wk with 3 tanks per treatment and 15 yellow perch per tank. No mortality or HDPE accumulation in the fish was found in any treatments. Weight gain and condition factor of fish were not significantly impacted by HDPE (P > 0.05). Compared to the control group, fish fed the 8% HDPE diet had significantly decreased levels of protein and ash (P < 0.05). In response to the increasing levels of HDPE exposure, the hepatosomatic index value, hepatocyte size, and liver glycogen level were increased, but lipid content was reduced in the liver tissues. Compared to the control treatment, fish fed the 8% HDPE diet had significant accumulations of total bile acids and different metabolism pathways such as bile acid biosynthesis, pyruvate metabolism, and carnitine synthesis. Significant enterocyte necrosis was documented in the foregut of fish fed the 2% or 8% HDPE diet; and significant cell sloughing was observed in the midgut and hindgut of fish fed the 8% HDPE diet. Fish fed the 2% HDPE diet harbored different microbiota communities compared to the control fish. This study demonstrates that HDPE ranging from 100 to 125 μm in feed can be evacuated by yellow perch with no impact on growth. However, dietary exposure to HDPE decreased whole fish nutrition quality, altered nutrient metabolism and the intestinal histopathology as well as microbiota community of yellow perch. The results indicate that extended exposure may pose a risk to fish health and jeopardize the nutrition quality of aquacultured end product. This hypothesis remains to be investigated further.

The Mechanisms and Physiological Consequences of Diurnal Hepatic Cell Size Fluctuations: A Brief Review.

Liver size in mammals fluctuates throughout the day and correlates with changes in hepatocyte size. However, the role of these daily changes in liver and hepatocyte size and the underlying molecular mechanisms remain largely unknown. In this review, we highlight the view that hepatocyte size, and thus, overall organ size, is subject to regulation by the circadian clock and feeding/fasting cycles. To that end, we provide an overview of the current literature dealing with this phenomenon and elaborate the role of feeding and nutrients in this process. We will discuss the role of hepatic protein content and synthesis, which are both subject to diurnal regulation, in daily hepatocyte and liver size fluctuations. Although there is evidence that changes in hepatocyte and liver size are associated with daily variations in macromolecule content, there is also evidence that these changes in size may be actively regulated by modifications of the cells' osmotic environment. Future research will need to examine the intriguing possibility that hepatocyte and liver size fluctuations may be required for normal liver function and to reveal the underlying molecular mechanisms behind this process.

Role of 4-Methylimidazole in Liver Toxicity

Background: These days, food products industry involves the commercial production and addition of food colors, which comprises many food dyes, including caramel colors. 4-methylimidazole (4-MEI) is a component of various caramel-colored food products such as bakery, beer, soft drinks, coffee and sauces, which are consumed daily. The most common route of exposure is ingestion and liver is the organ of detoxification. The histomorphometric observations in liver after 4-MEI consumption have not been reported to the best of our knowledge and so the present study have been designed to evaluate the same. Methodology: Adult male Wistar albino rats weighing 150–200 g were procured for the study and divided into the control and experimental groups. The experimental animals were given 4-MEI orally by gavage tube at a dose of 250 mg/kg body weight daily for 1 month, while the control animals received distilled water. At the end of experiment, all the animals were euthanized under ether anesthesia by perfusion with Formal saline. Dissection and histopathological processing of liver was done for the examination. Results: The histomorphometric observations of the liver in experimental rats revealed a significant increase in sinusoidal width indicative of sinusoidal dilatation and congestion. There was a significant increase in the size of hepatocytes while a decrease in the size of their nuclei was noted, suggestive of ballooning degeneration. Conclusion: The findings in the present study strongly suggest hepatocellular damage caused by ingestion of 4-MEI found in caramel color dyes used routinely in the food industry.

STRUCTURAL TRANSFORMATION OF CHICKEN LIVER UNDER THE INFLUENCE OF THE VIRAL FACTOR ON THE BACKGROUND OF MITOFEN APPLICATION

The paper presents the results of studies on histological and morphometric transformation in the liver of chickens during experimental infection with a virulent strain of infectious bursal disease virus (IBD) and the use of the antioxidant mitofen. It was found that during the experimental infection of chickens with the IBD virus strain, pathological processes associated with metabolic disorders were revealed in the liver of chickens – granular, fine-droplet fatty and vacuolar de-generation, as well as cell edema, deformation of the nucleus, the predominance of the stromal processes over paren-chymal ones. When using mitofen, the morphometric parameters were characterized by the normalization of the cellular components of the liver. At the same time, the size of hepatocytes increased, the number of binuclear cells increased, and the density of the content of liver cells per conventional unit of area increased.

Formimidoyltransferase cyclodeaminase prevents the starvation-induced liver hepatomegaly and dysfunction through downregulating mTORC1.

The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.

Influence of heavy metals on physiological and biochemical parameters of Pseudorasbora parva (Cypriniformes, Cyprinidae)

Anthropogenic load on aquatic ecosystems leads to increased inputs of heavy metals, which can have a toxic effect on aquatic organisms. Some of the most appropriate objects for research are short-cycle fish species. This article considers the results of studies on the adaptive reactions of the stone moroko Pseudorasbora parva (Temminck et Schlegel, 1846) to Mn, Pb, Ni heavy metal ions, which exceeded the reference values in the reservoir by 1.7, 1.5 and 2.0 times, respectively. Changes in morphological parameters of the blood and histocytological pattern of the hepatopancreas of the experimental species under the influence of toxicants, as well as changes in biochemical parameters, were determined. It was noted that the influence of Mn caused pathological changes in the form of poikilocytosis. The morphometric parameters of erythrocytes (the cell area and the nuclear area) reached 67.48 ± 0.67 and 13.97 ± 0.22 µm2 respectively (4.0% and 13.8% less compared to the control). The influence of Ni resulted in an increased number of leukocytes and immature forms of erythrocytes. The area of erythrocytes was 0.9% smaller than that of the control group, and the area of the nucleus was 4.5% smaller than in the control. The effect of Pb as well as Mn consisted in poikilocytosis. The area of red blood cells and nuclei was smaller by 6.5% and 8.3%, respectively, compared to the control. The percentage of white blood cells in fish exposed to Ni and Pb tended to increase. In the experiment with nickel, the percentage of white blood cells was 10.2% of the number of formed elements; in the experiment with lead – 11.3%; with manganese – 6.1%, while in the control, the number of white blood cells compared to the total number of formed elements of fish was only 1.2%. Cytometric studies have revealed that there are significant differences in the shape, size, and location of hepatocytes in different experimental fish. The structural components of the liver for histological specimens were stained differentially with different intensities and different colours. The hepatocytes on histological specimens of the liver of the stone moroko exposed to Ni and Mn ions did not have clearly defined boundaries, there was a large number of destroyed cells, which indicates the toxic effect of these heavy metals. The hepatocytes exposed to Pb had the largest area of cells and nuclei and the highest nuclear-cytoplasmic ratio is typical for hepatocytes under the influence of Mn. The nuclei had the largest size and occupied 12.7% of the internal contents of the cells. It is shown that under the impact of the studied concentrations of Mn, Ni and Pb, lactate dehydrogenase activity increased by 1.22, 1.14 and 1.48 times compared to the control, respectively. In contrast, there was a 3.27-fold decrease in succinate dehydrogenase activity under the impact of Mn. Besides that, the activity of the enzyme decreased by 1.48 and 1.68 times under the action of Ni and Pb. Subsequently, we found an increase in the activity of alkaline phosphatase in muscle tissue by 3.25–3.94 times under the influence of the studied toxicants. Muscle protein levels under the impact of Mn were 1.14 times lower than in the control, the most distinct decrease in protein was found under the impact of Ni (1.53 times). The obtained data of physiological and biochemical reactions of the stone moroko to the influence of heavy metals provide an opportunity to predict changes in the species composition of fish fauna under conditions of excessive toxic pollution of ecosystems.

Effects of dietary Astragalus membranaceus (Fisch.) Bge. root extract on growth performance, plasma biochemical parameters, fish composition, liver and intestinal morphology, and genes expression in head kidney of hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀)

In recent years, plant extracts have been paid more and more attention as immune enhancers for aquatic animals instead of antibiotics. In the present study, the effects of Astragalus membranaceus extract on growth performance, body composition, plasma biochemistry analysis, intestinal and liver histology and gene expression were investigated in hybrid groupers (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀). Five groups of experimental diets were prepared by adding different levels (0%, 0.1%, 0.2%, 0.4%, and 0.8%) of Astragalus extract in the basal diet. Samples were collected at the end of the 8-week feeding experiment. The results showed that Astragalus extract (AE) had no significant effect on the weight gain rate and feed efficiency ratio of hybrid grouper (P > 0.05). There were no significant difference of the contents of crude protein, crude lipids, moisture and ash in the whole body and muscle of hybrid groupers (P > 0.05). The villous structure of the foregut and midgut, the hepatocyte size and the integrity of cell membrane in each experimental group has no significant changes too. The changes of villus length in the hindgut becomes longer as the increases of AE addition. The addition of 0.1% and 0.2% of AE significantly reduced serum cholesterol content (P < 0.05). The relative mRNA expressions of Caspase 9, Keap1 and IL-8 in head kidney of fish showed a significant increase trend with the addition of AE (P < 0.05). The results showed that dietary AE could not significantly improve the growth performance and liver morphology even though could improve hindgut morphology of hybrid grouper.

Hepatocytes Protection by Vitamin E in Alcoholic Liver Injury: A Light Microscopic Study

Background: Alcohol induces histomorphological changes in the liver and vitamin E has a protective role against these changes. Objective: To observe changes in hepatocytes of rabbits exposed to intragastric administration of alcohol and the protective role of vitamin E against these changes. Study Design: Analytical experimental study Place and Duration of Study: Department of Anatomy, Pathology and Pharmacology of Peshawar Medical College, Peshawar, Pakistan from 1st January 2016 to 30th June 2016. Methodology: Eighteen male rabbits domestic type (Oryctolaguscuniculus) were included. Experimental duration for category E8 animals was 8 weeks while for category E4 animals it was 4 weeks. The groups were, control group A in which animals were given proper food and normal saline as drinking water, experimental group B in which animals were fed on proper diet and 30% ethanol solution (30 ml/kg/day) orally daily with normal saline and experimental group C in which animals were treated with proper diet, 30% ethanol solution (30 ml/kg/day), vitamin E (50 mg/kg/day) orally daily and normal saline as drinking water. Results: The difference in the ALT, hepatocyte count and size and hepatocyte nuclear count and size of control and experimental groups and experimental group B-II and C-II from both category E4 and E8 showed a highly significant P values. Conclusion: Alcohol causes histomorphological changes in the liver even in the short period of 4-8 weeks and these changes can be minimized by the antioxidant action of vitamin E. Keywords: Alcohol, Liver, Histomorphology, Vitamin E, Hepatocyte, ALT

Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115.

Background & AimsRecently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model.Methods and ResultsPatients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity.ConclusionsOur data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.

Effects of alternative and sustainable ingredients, insect meal, microalgae and protein and lipid from tuna cooking water, on meagre (Argyrosomus regius) growth, food conversion and muscle and liver composition

This study aimed to evaluate the effects of alternative feed ingredients: Insect meal (DI) using non-defatted meal obtained from Acheta domesticus, Microalgae (DM) using a mix of four marine microalgae ((Nannochloropsis gaditana, Tisochrysis lutea, Rhodomonas lens, Isochrysis galbana), Protein and oil from water of tuna canning process (DP&L) and a Mixture (DMix) of the three ingredients, on the growth, feed utilisation, digestibility and composition of meagre juveniles, and the results obtained were compared with a feed similar to a commercial feed used as a control (DC). Results show that the formulated alternative feeds had different effects on fish growth. DMix have a similar growth performance than the control, whereas the other treatments (DI, DM and DP&L) showed a lower final weight. Hepatosomatic and viscerosomatic indices did not show differences among the treatments. Muscle protein content was higher for fish fed with DMix group whereas lipids were significantly higher in DI. In the case of the liver, protein was higher in the liver of fish fed with DI, DM and DP&L, whereas lipids were higher in fish fed with DI and DM, a result that was confirmed with the results obtained in hepatocyte size and lipid accumulation.The nutritional value of the meagre muscle at the end of the study showed that meagre fed with DM and DI diets contained a significantly higher content of monounsaturated and n-6 PUFA, whereas fish from the groups fed with DP&L and DMix had a significantly higher content of DHA and n-3 PUFA with the liver showing similar results. In view of the results obtained, the ingredients assayed in this study might be used as alternative sources of protein and lipids in aquafeeds since no negative effects were detected neither on fish growth, muscle composition or final nutritional value, except in the case of the diet with microalgae (DM), which inclusion rate in the feed must be adjusted and needs more research.

Early Weaning Affects Liver Antioxidant Function in Piglets.

Simple SummaryEarly weaning is used to improve efficiency in pig production. However, early weaning may trigger liver oxidative stress in piglets. In this study, we evaluated the effects of early weaning on the development and antioxidant function of the liver in piglets. Our findings show that early weaning significantly decreases piglet body weight and suppresses liver development. We find that early weaning also suppresses the activities of superoxide dismutase (SOD) and catalase (CAT) (p < 0.05). It could be concluded that weaning may reduce the growth performance and liver antioxidant function of piglets.This study examined the impact of early weaning on antioxidant function in piglets. A total of 40 Duroc × Landrace × Large White, 21-day-old piglets (half male and half female) were divided into suckling groups (SG) and weaning groups (WG). Piglets in WG were weaned at the 21st day, while the piglets in SG continued to get breastfed. Eight piglets from each group were randomly selected and slaughtered at 24th-day (SG3, WG3) and 28th-day old (SG7, WG7). The body weight, liver index, hepatocyte morphology, antioxidant enzymes activity, gene expression of antioxidant enzymes, and Nrf2 signaling in the liver of piglets were measured. The results showed that weaning caused decreased body weight (p < 0.01), lower liver weight (p < 0.01), and decreased the liver organ index (p < 0.05) of piglets. The area and size of hepatocytes in the WG group was smaller than that in the SG group (p < 0.05). We also observed that weaning reduced the activity of superoxide dismutase (SOD) and catalase (CAT) (p < 0.05) in the liver of piglets. Relative to the SG3 group, the gene expression of GSH-Px in liver of WG3 was significantly reduced (p < 0.05). The gene expression of Nrf2 in the SG3 group was higher than that in the WG3 group (p < 0.01). The gene expression of NQO1 in the SG7 group was higher than that in the WG7 group (p < 0.05). In conclusion, weaning resulted in lower weight, slowed liver development, and reduced antioxidant enzymes activity, thereby impairing liver antioxidant function and suppressing piglet growth.

Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy.

Background & AimsMaternal liver shows robust adaptations to pregnancy to accommodate the metabolic needs of the developing and growing placenta and fetus by largely unknown mechanisms. We found that Ascl1, a gene encoding a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice.MethodsTo investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from midgestation until term.ResultsAs a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 showed aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and increased release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta showed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 showed robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments.ConclusionsIn summary, we show that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies show that Ascl1 is a novel and critical regulator of the physiology of pregnancy.