Hepatic Fat Accumulation Research Articles

Dysbiosis and nutrition in steatotic liver disease: addressing the unrecognized small intestinal bacterial overgrowth (SIBO) challenge.

Steatotic liver disease (SLD) is characterized by hepatic fat accumulation, potentially causing major consequences such as liver decompensation. Currently, we lack medications for the treatment of SLD. Therapeutic recommendations for patients include a hypocaloric diet, weight loss, and physical activity. In particular, the Mediterranean diet is frequently recommended. However, this diet might exacerbate intestinal problems in a subset of patients with coexisting small intestinal bacterial overgrowth (SIBO). Previous studies have reported that SIBO is more predominant in patients with fatty liver than in healthy individuals. Both our research and the findings of others have highlighted a challenge related to nutritional therapy in patients with fatty liverwho also suffer from SIBO inasmuch as SIBO induces several phenomena (like bloating or abdominal pain) that can adversely affect patients' quality of life and might be exacerbated by the Mediterranean diet. This may lower their adherence to the intervention. As a solution, we suggest introducing additional diagnostics (e.g., breath test) in patients with SLD who complain of SIBO-like symptoms. The next step is to modify their diets temporarily starting with several weeks of "elimination and sanitation." This would involve restricting products rich in fermentable sugars and polyols, while simultaneously treating the bacterial overgrowth. In summary, while the hypocaloric Mediterranean diet is beneficial for patients with fatty liver, those with coexisting SIBO may experience exacerbated symptoms. It is vital to consider additional diagnostics and dietary modifications for this subset of patients to address both liver and intestinal health concurrently.

Altered lipid metabolism and the development of metabolic-associated fatty liver disease.

An increasing amount of research has underscored the significant role of lipoproteins in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). This comprehensive review examines the intricate relationship between lipoprotein abnormalities and the development of MAFLD. Atherogenic dyslipidemia seen in insulin resistance states play a significant role in initiating and exacerbating hepatic lipid accumulation. There are also specific genetic factors ( PNPLA3 , TM6SF2 , MBOAT7 , HSD17B13 , GCKR- P446L) and transcription factors (SREBP-2, FXR, and LXR9) that increase susceptibility to both lipoprotein disorders and MAFLD. Most monogenic primary lipid disorders do not cause hepatic steatosis unless accompanied by metabolic stress. Hepatic steatosis occurs in the presence of secondary systemic metabolic stress in conjunction with predisposing environmental factors that lead to insulin resistance. Identifying specific aberrant lipoprotein metabolic factors promoting hepatic fat accumulation and subsequently exacerbating steatohepatitis will shed light on potential targets for therapeutic interventions. The clinical implications of interconnection between genetic factors and an insulin resistant environment that predisposes MAFLD is many fold. Potential therapeutic strategies in preventing or mitigating MAFLD progression include lifestyle modifications, pharmacological interventions, and emerging therapies targeting aberrant lipoprotein metabolism.

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis.

The gut microbiota plays an important role in the development of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unclear. It has been found that the transcription factor XBP1s plays an important role in regulating inflammation and lipid metabolism and maintaining the integrity of intestinal barrier. However, whether XBP1s modulates the development of NASH by regulating the integrity of the intestinal barrier and altering the composition of the gut microbiota remains unknown. Mice fed with a fat-, fructose-, cholesterol-rich (FFC) diet for 24 weeks successfully established the NASH model, as demonstrated by significant hepatic steatosis, inflammation, hepatocyte injury and fibrosis. The profile of gut microbiota dynamically changed with the different stages of NAFLD via 16S rDNA sequencing the feces from mice fed with FFC diet for 0, 12, or 24 weeks or NASH mice treated with siRNA-loaded folic acid-modified TPGS (hereafter named FT@XBP1). NASH mice had significantly higher abundance of Firmicutes, Blautia and Bacteroides, and lower abundance of Bifidobacterium and GCA-900066575. FT@XBP1 supplementation had a significantly attenuated effect on FFC diet-induced weight gain, hepatic fat accumulation, dyslipidemia, inflammatory cytokines, ER stress and fibrosis. In particularly, FT@XBP1 modulates the composition of the intestinal flora; for example, NASH mice demonstrated higher abundance of Blautia and Bacteroides, and lower abundance of Actinobacteriota, Muribaculaceae and Bifidobacterium, which were partially restored by FT@XBP1 treatment. Mechanistically, FT@XBP1 increased the expression of ZO-1 in the intestine and had the potential to restore intestinal barrier integrity and improve antimicrobial defense to alleviate enterogenic endotoxemia and activation of inflammatory signaling pathways. Regulation of the key transcription factor XBP1s can partially restore the intestinal microbiota structure, maintain the integrity of intestinal mucosal barrier, and prevent the progression of NASH, providing new evidence for treating NASH.

Bacillus coagulans regulates gut microbiota and ameliorates the alcoholic-associated liver disease in mice.

Alcoholic-associated liver diseases (ALD) are now widespread issues worldwide. Alcoholic-induced chronic dysbiosis of the gut microbiota is one of the factors in the pathophysiology of ALD. In this work, we employed a chronic-binge ethanol feeding mice model, as described in a previous report. Our findings demonstrate that hepatic inflammatory injury damage and accumulation of fat can be effectively reduced in mice with ALD by altering the gut microbiota utilizing Bacillus coagulans. Treatment with B. coagulans significantly modulates the levels of TNF-α, IL-1β, and IL-22 cytokines while maintaining tight junction proteins and mucin protein expressions to support intestinal barrier function restoration. Treatment with B. coagulans also alters the composition of the gut microbiota and increases the production of short-chain fatty acids (SCFAs). This is mostly due to B. coagulans promotes the growth of bacteria that produce SCFAs, such as Ruminococcus species and Akkermansia, while inhibiting the growth of pathogenic bacteria like Escherichia Shigella. Moreover, treatment with B. coagulans causes levels of 2-Ketobutyric acid, ketoleucine, and indoleacetic acid increase while homovanillic acid and 3'-O-Methylguanosine metabolites decrease significantly. This study facilitates the development of therapeutic and preventive strategies for ALD using lactic acid bacteria.

Apical papilla stem cell-derived exosomes regulate lipid metabolism and alleviate inflammation in the MCD-induced mouse NASH model

Stem cells from the apical papilla(SCAPs) exhibit remarkable tissue repair capabilities, demonstrate anti-inflammatory and pro-angiogenic effects, positioning them as promising assets in the realm of regenerative medicine. Recently, the focus has shifted towards exosomes derived from stem cells, perceived as safer alternatives while retaining comparable physiological functions. This study delves into the therapeutic implications of exosomes derived from SCAPs in the methionine-choline-deficient (MCD) diet-induced mice non-alcoholic steatohepatitis (NASH) model. We extracted exosomes from SCAPs. During the last two weeks of the MCD diet, mice were intravenously administered SCAPs-derived exosomes at two distinct concentrations (50 μg/mouse and 100 μg/mouse) biweekly. Thorough examinations of physiological and biochemical indicators were performed to meticulously evaluate the impact of exosomes derived from SCAPs on the advancement of NASH in mice induced by MCD diet. This findings revealed significant reductions in body weight loss and liver damage induced by the MCD diet following exosomes treatment. Moreover, hepatic fat accumulation was notably alleviated. Mechanistically, the treatment with exosomes led to an upregulation of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) levels in the liver, enhancing hepatic fatty acid oxidation and transporter gene expression while inhibiting genes associated with fatty acid synthesis. Additionally, exosomes treatment increased the transcription levels of key liver mitochondrial marker proteins and the essential mitochondrial biogenesis factor. Furthermore, the levels of serum inflammatory factors and hepatic tissue inflammatory factor mRNA expression were significantly reduced, likely due to the anti-inflammatory phenotype induced by exosomes in macrophages. The above conclusion suggests that SCAPs-exosomes can improve NASH.

Microbial Dysbiosis Linked to Metabolic Dysfunction-Associated Fatty Liver Disease in Asians: Prevotella copri Promotes Lipopolysaccharide Biosynthesis and Network Instability in the Prevotella Enterotype.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by hepatic fat accumulation by metabolic dysfunction. The rising prevalence of MAFLD, especially among Asians, may be associated with changes in gut microbiota. We investigated gut microbiota characteristics and potential mechanisms leading to MAFLD development according to enterotypes. Case-control studies examining the gut microbiota composition between MAFLD and non-MAFLD participants were searched in public databases until July 2023. Gut microbiota was categorized into two enterotypes by principal component analysis. According to the enterotypes, LEfSe, ALDEx2, XGBoost, and DCiPatho were utilized to identify differential abundances and pathogenic microbes in the gut between the MAFLD and non-MAFLD groups. We analyzed microbial community networks with the SprCC module and predicted microbial functions. In the Prevotella enterotype (ET-P), 98.6% of Asians and 65.1% of Caucasians were associated with MAFLD (p = 0.049). MAFLD incidence was correlated with enterotype, age, obesity, and ethnicity (p < 0.05). Asian MAFLD patients exhibited decreased Firmicutes and Akkermansia muciniphila and increased Bacteroidetes and P. copri. The pathogenicity scores were 0.006 for A. muciniphila and 0.868 for P. copri. The Asian MAFLD group showed decreased stability and complexity in the gut microbiota network. Metagenome function analysis revealed higher fructose metabolism and lipopolysaccharide (LPS) biosynthesis and lower animal proteins and α-linolenic acid metabolism in Asians with MAFLD compared with the non-MAFLD group. LPS biosynthesis was positively correlated with P. copri (p < 0.05). In conclusion, P. copri emerged as a potential microbial biomarker for MAFLD. These findings enhance our understanding of the pathological mechanisms of MAFLD mediated through the gut microbiota, providing insights for future interventions.

Fish oil consumption prevents hepatic lipid accumulation induced by high-cholesterol feeding in obese KK mice.

Fish oil (FO) is rich in the n-3 polyunsaturated fatty acids. It has been demonstrated that FO intake possesses lipid-lowering properties. Conversely, a high-cholesterol (CH) diet promotes lipid accumulation in the liver and induces fatty liver. This study investigated the effects of FO feeding on hepatic lipid accumulation induced by high-cholesterol feeding in KK mice. All experimental diets had a fat energy ratio of 25%, the SO group had all fat sources as safflower oil (SO), the 12.5 FO group had half of the SO replaced with FO, and the 25 FO group had all of the SO replaced with FO, each with or without 2 weight % (wt%) cholesterol (SO/CH, 12.5 FO/CH, and 25 FO/CH groups, respectively), for 8 weeks. The hepatic triglyceride and total cholesterol levels were significantly lower in the 25 FO/CH group than in the SO/CH group. The hepatic mRNAs of fatty acid synthesis-related genes were downregulated by the FO feeding groups. In view of importance to establish the benefit of FO for preventing severe NAFLD, our results suggest that FO intake prevents excessive hepatic fat accumulation induced by a high-cholesterol diet in obese KK mice through the inhibition of fatty acid synthesis.

Genistein and sex hormone treatment alleviated hepatic fat accumulation and inflammation in orchidectomized rats with nonalcoholic steatohepatitis

Testosterone deficiency has been reported to accelerate nonalcoholic fatty liver disease (NAFLD). However, there are minimal data on the risk of NAFLD in transgender women and the treatment of NAFLD in this population. This study aimed to investigate the treatment effects and the mechanisms of action of genistein and sex hormones in orchiectomized (ORX) rats with nonalcoholic steatohepatitis (NASH) induced by a high fat high fructose diet (HFHF). Seven-week old male Sprague-Dawley rats were randomly divided into 7 groups (n = 6 each group); 1) control group, 2) ORX + standard diet group, 3) HFHF group, 4) ORX + HFHF group, 5) ORX + HFHF diet + testosterone group (50 mg/kg body weight (BW) once weekly), 6) ORX + HFHF diet + estradiol group (1.6 mg/kg BW daily), and 7) ORX + HFHF diet + genistein group (16 mg/kg BW daily). The duration of treatment was 6 weeks. Liver tissue was used for histological examination by hematoxylin and eosin staining and hepatic fat measurement by Oil Red O staining. Protein expression levels of histone deacetylase3 (HDAC3) and peroxisome proliferator-activated receptor delta (PPARδ) were analyzed by immunoblotting. Hepatic nuclear factor (NF)-ĸB expression was evaluated by immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, hepatocyte ballooning and the highest percentage of positive Oil Red O staining area among all groups. The expression of HDAC3 and PPARδ was downregulated, while NF-ĸB expression was upregulated in the ORX + HFHF group when compared with control and ORX + standard diet groups. Testosterone, estradiol and genistein treatment improved histological features of NASH together with the reversal of HDAC3, PPARδ and NF-ĸB protein expression comparing with the ORX + HFHF group. In summary, genistein and sex hormone treatment could alleviate NASH through the up-regulation of HDAC3 and PPARδ, and the suppression of NF-ĸB expression.

Dietary Tomato Pectin Attenuates Hepatic Insulin Resistance and Inflammation in High-Fat-Diet Mice by Regulating the PI3K/AKT Pathway

Chronic metabolic disease is a serious global health issue, which is accompanied by impaired insulin resistance. Tomato pectin (TP) is a naturally soluble complex hetero-polysaccharide with various biological functions. However, the impact of TP on hepatic insulin resistance in a high-fat diet (HFD) and its potential mechanism remains largely unknown. The results revealed that TP treatment significantly decreased the liver weight, hepatic fat accumulation and hepatic injury in HFD-fed mice. TP also improved fasting blood glucose levels and glucose tolerance in HFD-fed mice. The underlying mechanisms involved in the inflammation, oxidative stress and insulin signaling in the liver were also investigated by RT-qPCR and western blot, which indicated that TP ameliorated hepatic insulin resistance by regulating the PI3K/AKT/GSK-3β pathway, increasing the expression of GLUT4, decreasing the expression of PECK and G6P as well as restoring antioxidant activities and suppressing the inflammation statues in HFD-fed mice. Our data showed that dietary TP has profound effects on hepatic insulin resistance, inflammation and oxidative stress, demonstrating that TP might be a promising therapeutic agent against insulin resistance and related chronic metabolic disease.

Molecular characterization of Fusarium venenatum-based microbial protein in animal models of obesity using multi-omics analysis

Microbial protein, produced by fermentation of Fusarium venenatum is a promising candidate alternative protein source. Previous study has demonstrated its ability to improve hyperlipidemia in rats, yet the related mechanism remains unclear. In this study, we aimed to evaluate the potential of F. venenatum as an alternative protein source and its impact on lipid metabolism using multi-omics analysis. Initial experiments with Caenorhabditis elegans revealed that F. venenatum enhanced longevity, improved immune responses, and reduced lipid metabolism by downregulating fat synthesis-related genes. Subsequently, we conducted experiments with mice on a high-fat diet to confirm the anti-obesity effects of F. venenatum. The groups fed F. venenatum showed improved lipid profiles and reduced hepatic fat accumulation. Furthermore, fecal metabolomic analysis showed higher excretion of primary bile acid and cholesterol in the groups fed F. venenatum which might lead to a decrease in lipid digestion and hepatic fat accumulation. Collectively, this series of experiments revealed the potential of F. venenatum as a sustainable alternative protein and its application as an anti-obesity supplement.

Inhibitory Effects of Jiuzao Polysaccharides on Alcoholic Fatty Liver Formation in Zebrafish Larvae and Their Regulatory Impact on Intestinal Microbiota.

The liver is critical in alcohol metabolism, and excessive consumption heightens the risk of hepatic damage, potentially escalating to hepatitis and cirrhosis. Jiuzao, a by-product of Baijiu production, contains a rich concentration of naturally active polysaccharides known for their antioxidative properties. This study investigated the influence of Laowuzeng Jiuzao polysaccharide (LJP) on the development of ethanol-induced alcoholic fatty liver. Zebrafish larvae served as the model organisms for examining the LJPs hepatic impact via liver phenotypic and biochemical assays. Additionally, this study evaluated the LJPs effects on gene expression associated with alcoholic fatty liver and the composition of the intestinal microbiota through transcriptomic and 16 S rRNA gene sequencing analyses, respectively. Our findings revealed that LJP markedly mitigated morphological liver damage and reduced oxidative stress and lipid peroxidation in larvae. Transcriptome data indicated that LJP ameliorated hepatic fat accumulation and liver injury by enhancing gene expression involved in alcohol and lipid metabolism. Furthermore, LJP modulated the development of alcoholic fatty liver by altering the prevalence of intestinal Actinobacteriota and Firmicutes, specifically augmenting Acinetobacter while diminishing Chryseobacterium levels. Ultimately, LJP mitigated alcohol-induced hepatic injury by modulating gene expression related to ethanol metabolism, lipid metabolism, and inflammation and by orchestrating alterations in the intestinal microbiota.

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.

Kiwifruit Peel Extract Improves the Alterations in Lipid Metabolism in High-fat Diet-fed Model Rats.

Previous studies have demonstrated that the kiwifruit peel, which is usually discarded by consumers and factories, has the highest polyphenol content among all parts of the kiwifruit. To maximize the utilization of these waste resources, the aim of this study was to examine the regulatory effects of polyphenols extracted from kiwifruit peel (KPE) on lipid metabolism and investigate their underlying mechanisms. Thirty-two male Sprague‒Dawley rats were divided into four groups: those fed a normal diet, those fed a high-fat (HF) diet, and those fed a HF diet with a low dose of KPE solution (50 mg/kg) or a high dose of KPE (100 mg/kg) by gavage. The findings of the study revealed that KPE effectively reduced body weight gain and the increases in triglycerides and total cholesterol in serum induced by the HF diet (HFD). Additionally, KPE supplementation led to a significant decrease in hepatic fat accumulation, potentially by increasing hepatic oxidation abilities. Hepatic lipidomics demonstrated that KPE influenced various metabolic pathways, including linoleic acid metabolism, steroid biosynthesis, and the biosynthesis of unsaturated fatty acids in HFD-induced rats, which were associated with the downregulation of FATP2, ACC, FAS, GPAT, DGTA1, DGTA2, and PPARγ expression as well as the upregulation of AMPK, PGC-1α, CPT-1, and PPARα expression. These findings suggest that KPE has considerable regulatory effects in rats with dyslipidaemia, which may provide supporting information for the reuse of kiwifruit peel.

Effects of quercetin and hydroxytyrosol supplementation in a high-fat diet on growth, lipid metabolism, and mitochondrial function in spotted seabass (Lateolabrax maculatus)

Endoplasmic reticulum (ER) stress and mitochondrial impairment commonly occur during the progression of fatty liver disease. There is a close connection and crosstalk between mitochondria and ER. The potential positive influence of mitigating ER stress (ERS) and mitochondrial damage in the context of preventing and treating fatty liver was explored in spotted seabass (Lateolabrax maculatus) as a susceptible model to fatty liver. A normal-fat diet (11% fat, NFD) and a high-fat diet (17% fat, HFD) were formulated and three additional diets were prepared by supplementation of quercetin (QUE) (0.1%), hydroxytyrosol (HT) (0.02%) or their combination (0.1% QUE + 0.02% HT) to the HFD (HFD + QUE HFD + HT and HFD + QUE + HT diets).Three replicate groups of fish (25 ± 0.02 g) were fed the test diets to visual satiety for 8 weeks. The results revealed the deterioration of growth, feed intake and feed utilization in HFD group compared to the NFD group whereas QUE and HT application improved their values and the optimum results were achieved for the HFD + QUE + HT group. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and both serum and hepatic triglyceride (TG), total cholesterol (T-CHO) and non-esterified free fatty acids (NEFA) concentrations were enhanced in HFD group, and their values decreased by QUE and HT, particularly their combined supplementation. The results of oil red O staining exhibited a remarkable reduction in number of lipid droplets in the liver of fish from HFD + QUE + HT group compared to the HFD group. Whole-body and muscle fat contents and abdominal fat index decreased by QUE and HT application. Expression of lipid metabolism related genes (srebp-1c, fas, acc) were down-regulated by QUE and HT treatment. Co-supplementation of QUE and HT down-regulated the expression of ERS-related genes (grp78, chop, perk, atf6, ire1), improved ER ultrastructure, and enhanced the coupling between mitochondria and ER. Moreover, expression of genes associated with hepatic mitochondrial biogenesis (pgc1-α, pgc1-β, nrf1) and mitophagy (pink1, atg5, mul1) was up-regulated in HFD + QUE, HFD + HT and HFD + QUE + HT groups. These data suggest that combined supplementation of QUE and HT in HFD for spotted seabass can improve growth and feed utilization, reduce hepatic damage and fat accumulation, and alleviate HFD induced ERS and mitochondrial dysfunction.

Lipogenic stearoyl-CoA desaturase-1 (SCD1) targeted virtual screening for chemical inhibitors: molecular docking / dynamics simulation and in vitro assessment of anti-NAFLD efficacy.

Amidst rising global prevalence of metabolic syndrome, the associated risk of non-alcoholic fatty liver disease (NAFLD) is also rapidly increasing. The pathogenesis of NAFLD starts with fat accumulation and progresses through inflammation and fibrotic sequel, often involving complex molecular mechanisms involving de novo lipogenesis. Stearoyl-CoA desaturase 1 (SCD1) enzyme, expressed in liver and adipose tissue, converts saturated fatty acids to monounsaturated fatty acids (MUFAs), contributing to triglyceride and cholesterol ester formation. In this study, potential SCD1 inhibitors were screened using the ZINC database of curated medically-approved drugs by virtual screening, molecular docking, and molecular dynamics simulations. The top-scoring five ligands with strong binding affinity against SCD1 were ZINC000003831151 > ZINC000001540998 > ZINC000003830713 > ZINC000000897251 > ZINC000002005305, which showed stable protein-ligand complexation and favorable pharmacokinetic attributes. The top ligand, Montelukast, was experimentally validated for its pharmacological efficacy in an in vitro cell culture model of steatosis (NAFLD). Montelukast showed a dose-dependent decrease in hepatic fat accumulation, reduced levels of free radicals, and lowered oxidative stress (P < 0.05). These outcomes suggest Montelukast to be a potential SCD1 inhibitor, with anti-NAFLD efficacy. These findings open new avenues for therapeutic development of the top 5 ligands in metabolic disorders involving SCD1.

Improvement of hepatic innate immunity in chemically-injured livers to develop hepatocarcinoma by a serine type-protease inhibitors enriched extract from Chenopodium quinoa.

Food ingredients have critical effects on the maturation and development of the immune system, which innate - lymphoid (ILCs) and myeloid - cells play key roles as important regulators of energy storage and hepatic fat accumulation. Therefore, the objective of this study is to define potential links between a dietary immunonutritional induction of the selective functional differentiation of monocytes-derived macrophages, ILCs and lipid homeostasis in hepatocarcinoma (HCC)-developing mice. Hepatic chemically injured (diethylnitrosamine/thiacetamide) Rag2-/- and Rag2-/-Il2-/- mice were administered with serine-type protease inhibitors (SETIs) obtained from Chenopodium quinoa. Early HCC-driven immunometabolic imbalances (infiltrated macrophages, glucose homeostasis, hepatic lipid profile, ILCs expansion, inflammatory conditions, microbiota) in animals put under a high-fat diet for 2 weeks were assessed. It was also approached the potential of SETIs to cause functional adaptations of the bioenergetics of human macrophage-like cells (hMLCs) in vitro conditioning their capacity to accumulate fat. It is showed that Rag2-/-Il2-/- mice, lacking ILCs, are resistant to the SETIs-induced hepatic macrophages (CD68+F4/80+) activation. Feeding SETIs to Rag2-/- mice, carrying ILCs, promoted the expansion towards ILC3s (CD117+Nkp46+CD56+) and reduced that of ILC2s (CD117+KLRG1+) into livers. In vitro studies demonstrate that hMLCs, challenged to SETIs, develop a similar phenotype of that found in mice and bioenergetic adaptations leading to increased lipolysis. It is concluded that SETIs promote liver macrophage activation and ILCs adaptations to ameliorate HCC-driven immunometabolic imbalances.

Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation in individuals consuming little or no alcohol, has become highly prevalent globally. Oxidative stress plays a central role in instigating inflammation and cell death pathways driving NAFLD progression. This case-control study aimed to elucidate the association between circulating levels of the pivotal non-enzymatic antioxidants - coenzyme Q10 and vitamins E and C - and liver injury parameters among 60 Iraqi NAFLD patients versus 30 healthy controls. NAFLD diagnosis entailed over 5% hepatic steatosis on ultrasound excluding other etiologies. Patients spanned three age groups: 20-29, 30-39, and 40-49. Substantially diminished antioxidant levels concurrent with elevated alkaline phosphatase enzyme were unveiled in NAFLD patients relative to controls (all p < 0.001). Age-based analysis reinforced widespread antioxidant depletion and liver enzyme augmentation across NAFLD patients. Significant correlations also emerged between antioxidants and liver parameters. Our novel observations confirm an antioxidant inadequacy likely perpetuating pathogenic oxidative reactions in NAFLD. Restoring such deficits through lifestyle or therapeutic interventions may confer preventative and disease-modifying value.

Protocatechuic acid alleviates TMAO-aggravated atherosclerosis via mitigating inflammation, regulating lipid metabolism, and reshaping gut microbiota.

Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study investigated the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD + 0.2% TMAO diet (WDT), a WDT + 0.5% PCA diet (WDT + LPCA), and a WDT + 1.0% PCA diet (WDT + HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. The diet with PCA at 1% reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma pro-inflammatory cytokines. PCA also improved lipid metabolism by up-regulating the hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing the α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of the harmful Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.

Can dysmetabolic comorbidities carry hepatic fat accumulation in patients with inflammatory bowel diseases?

Can dysmetabolic comorbidities carry hepatic fat accumulation in patients with inflammatory bowel diseases?

Treatment with a new barbituric acid derivative suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice

IntroductionNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, often accompanied by obesity, diabetes, and increased risks of depression and anxiety. Currently, there are no FDA-approved drugs to treat NAFLD and its related systemic symptoms. Previously, we identified a new barbituric acid derivative (BA-5) that expressed effectiveness against fibrosis and drug-resistant hepatocellular carcinoma. AimsThis study investigated the potential of BA-5 against high-fat diet (HFD)-induced NAFLD and mood disorders in mice. Main methodsSix-weeks-old male C57BL/6 mice were fed with a 45 % HFD for 8 weeks to induce NAFLD and associated metabolic disorders. Mice were treated with a BA-5 and the therapeutic effects and the underlying molecular mechanisms were investigated. Key findingsAdministration of BA-5 significantly reduced serum levels of alanine aminotransferase (ALT), low-density lipoprotein (LDL), fatty acids (FA), and triglycerides (TG) in HFD-fed mice. BA-5 treatment decreased expressions of hepatic lipogenesis-related markers (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and ATP-citrate lyase (ACLY)), increased fatty acid oxidation markers (carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1)), and attenuated hepatic fat accumulation in HFD-fed mice. Moreover, HFD-induced adipocyte size enlargement and activation of lipolysis markers such as phosphorylated (p)-hormone-sensitive lipase (HSL) 565, p-HSL 660, and perilipin were inhibited in BA-5-treated mice. Notably, HFD-induced anxiety- and depression-like behaviors significantly improved in the BA-5 treated group through enhanced anti-inflammatory responses in the hippocampus. SignificanceThis study provides new insights into clinical therapeutic strategies of barbituric acid derivatives for HFD-induced NAFLD and associated mood disturbances.