Liver Metabolism Research Articles

Obesity and Hyperandrogenemia in Polycystic Ovary Syndrome: Clinical Implications.

Polycystic ovary syndrome (PCOS) is often accompanied with metabolic disturbances attributed to androgen excess and obesity, but the contribution of each has not been defined, and the occurrence of metabolic disturbances is usually not investigated. Ninety-nine women with PCOS and forty-one without PCOS were evaluated. The clinical biomarkers of alterations related to glucose (glucose, insulin, and clamp-derived glucose disposal - M), liver (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase), and endothelium (arginine, asymmetric dymethylarginine, carotid intima-media thickness, and flow-mediated dilation) metabolism were measured; participants were categorized into four groups according to their obesity (OB) and hyperandrogenemia (HA) status as follows: Healthy (no-HA, lean), HA (HA, lean), OB (no-HA, OB), and HAOB (HA, OB). Metabolic disturbances were very frequent in women with PCOS (≈70%). BMI correlated with all biomarkers, whereas free testosterone (FT) correlated with only glucose- and liver-related indicators. Although insulin sensitivity and liver enzymes were associated with FT, women with obesity showed lower M (coef = 8.56 - 0.080(FT) - 3.71(Ob); p < 0.001) and higher aspartate aminotransferase (coef = 26.27 + 0.532 (FT) + 8.08 (Ob); p = 0.015) than lean women with the same level of FT. Women with obesity showed a higher risk of metabolic disorders than lean women, independent of hyperandrogenemia. Clinicians are compelled to look for metabolic alterations in women with PCOS. Obesity should be treated in all cases, but hyperandrogenemia should also be monitored in those with glucose-or liver-related disturbances.

Electrochemical Activation of Metabolic Enzymes in Human Liver S9 Fractions

Human liver subcellular fractions such as liver microsomes, liver cytosol fractions, or S9 fractions are widely used in in-vitro assays to predict liver metabolism. The S9 fractions are the supernatants of human liver homogenates consist of both human liver microsomes and the cytosol. Therefore, these fractions contain majority of cytochrome P450 (CYP) enzymes and soluble phase II enzymes like glucuronosyltransferases, N-acetyl transferases, sulfotransferases, and glutathione-S-transferases. Here we report the direct electrochemistry and biocatalytic features of redox active enzymes impregnated in S9 fractions. We investigated the electrochemical properties of S9 films by immobilizing them onto a high purity graphite electrode and performing cyclic voltammetry in anaerobic (Ar saturated) and aerobic (O2 saturated) conditions. The electron transfer between the S9 film and the high purity graphite electrode was observed at the formal potential of -0.48 V, with respect to Ag/AgCl reference electrode, which confirmed the activation of CYP450 reductase enzyme in the film. These films also demonstrated a catalytic oxygen reduction with a maximum current density of ~0.5 mA cm-2 at the scan rate of 0.050V/s. We investigated the CYP activity in the S9 biofilm for phase 1 metabolism using diclofenac hydroxylation as a probe reaction and could able to identify metabolic products using liquid chromatography-mass spectrometry (LC-MS) technique. Eventually, we envision to develop a platform to perform both phase I and II metabolic reactions in a single electrochemical assay.

Dietary methylmercury and fatty acids affect the lipid metabolism of adipose tissue and liver in rainbow trout

Methylmercury (MeHg) is a pervasive environmental contaminant in aquatic ecosystems that can reach elevated concentrations in fish of high trophic levels, such as salmonids. The present study aims at investigating the individual and combined impacts of dietary MeHg and fatty acids on lipid metabolism in juvenile rainbow trout (Oncorhynchus mykiss) with a focus on two key organs, adipose tissue and liver. MeHg and fatty acids are both known to act on energy homeostasis although little is known about their interplay on lipid metabolism in fish. Fish were fed diets enriched in linoleic acid (LA, 18:2 n-6), α-linolenic acid (ALA, 18:3 n-3), eicosapentaenoic acid (EPA, 20:5 n-3) or docosahexaenoic acid (DHA, 22:6 n-3) for ten weeks, with the addition of MeHg to the diets during the last six weeks (0, 2.4 or 5.5 mg MeHg/kg dry matter). LA and ALA are polyunsaturated fatty acids (PUFA) typical of plant-derived oils whereas EPA and DHA are n-3 long chain PUFA largely found in fish oil, all used in feed formulation in aquaculture. The results showed that the LA-enriched diet induced a higher whole-body lipid content compared to the three other diets. On the contrary, the addition of MeHg led to a significant reduction of the whole-body lipid content, regardless of the diet. Interestingly, the adipocytes were larger both in presence of LA, compared to EPA and DHA, or MeHg, indicating a lipogenic effect of these two compounds. No effect was, however, observed on lipid accumulation per gram of adipose tissue. The fatty acid composition of adipose tissue and liver was significantly modified by the dietary lipids, reflecting both the fatty acid composition of the diets and the high bioconversion capacity of the rainbow trout. Exposure to MeHg selectively led to a release of n-6 PUFA from the hepatic membranes of fish fed the LA-enriched diet, showing a disruption of the pathways using n-6 PUFA. This study highlights the significant impact of MeHg exposure and dietary fatty acids on lipid metabolism in fish. Further investigation is needed to elucidate the underlying mechanisms and to explore the potential involvement of other organs.

New insights into the impact of polystyrene micro/nanoplastics on the nutritional quality of marine jacopever (Sebastes schlegelii)

Microplastics (MPs) and nanoplastics (NPs) are ubiquitous in the marine environments due to the wide use and mismanagement of plastics. However, the effect of MPs/NPs on the nutrition quality of economic species is poorly understood, and their underlying mechanisms remained unclear. We therefore investigated the impacts of polystyrene MPs/NPs on the nutrition composition of marine jacopever Sebastes schlegelii from the perspective of assimilation and metabolism. Results showed that NPs reduced more nutrition quality than MPs. Despite no notable impact on intestinal microbiota function, MPs/NPs influenced the assimilation of fish through intestinal damage. Furthermore, NPs induced greater damage to hepatocyte metabolism than MPs, caused by hepatocyte uptake through membrane protein pumps/channels and clathrin/caveolin-mediated endocytosis for NPs, while through phagocytosis/pinocytosis for MPs. NPs triggered more cell apoptosis signals in Ferroptosis and FoxO signaling pathways than MPs, destroying mitochondria structure. Compared with MP treatments, a significant upregulation of genes (PRODH and SLC25A25A) associated with the electron transfer chain of mitochondria was detected in the NP treatments, influencing the tricarboxylic acid cycle and interfering with liver metabolism of proteins, fatty acid, glycerol phospholipids, and carbohydrates. This work provides new insights into the potential impacts of MPs/NPs on the quality and safety of seafood.

Transcriptomics Reveal the Effects of Breeding Temperature on Growth and Metabolism in the Early Developmental Stage of Platax teira.

The growth, development, and survival of fish, especially in the early stages of development, is influenced by a complex of environmental factors, among which temperature is one of the most important. Although the physiological effects of environmental stress in fish have been extensively studied, the molecular mechanisms are poorly understood. However, recent advances in transcriptomic techniques have facilitated the study of the molecular mechanisms of environmental stress responses in aquatic species. Here, we aimed to elucidate the effects of breeding temperatures (21, 24, 27, and 30 °C) on the growth and nutrient metabolism in the early developmental stage of Platax teira, using transcriptomic techniques. Transcriptomic analysis identified 5492, 6937, and 4246 differentially expressed genes (DEGs) in the 21 vs. 24 °C, 27 vs. 24 °C, and 30 vs. 24 °C comparisons, respectively, most of which were involved in cell processes, single organism, metabolism, catalytic activity, and cell part, based on gene ontology (GO) functional annotations. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were mainly enriched in pathways related to metabolism of matter and energy, protein digestion and absorption, and glucose and lipid metabolism. Additionally, the expression of genes related to energy, lipid, and glucose metabolism in the fish liver was upregulated under a low-temperature condition (21 °C), although increasing the temperature within the acceptable threshold improved nutrient metabolism and growth in the fish. Meanwhile, nutrient metabolism and growth were suppressed by an extremely high temperature (30 °C) owing to oxidative stress. Overall, it was shown that nutrient metabolism pathways were involved in thermal stress responses in P. teira, and the optimal breeding temperature range was 24-27 °C. Through transcriptomics, the regulatory mechanism of larval development in P. teira under different growth temperatures was elucidated, with the goal of establishing a theoretical basis for industrial breeding.

Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion

Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.

Novel Multi-Ingredient Supplement Facilitates Weight Loss and Improves Body Composition in Overweight and Obese Individuals: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and facilitate weight loss. The objective of this study was to investigate the effects of a multi-ingredient nutritional supplement designed to facilitate mitochondrial function and metabolic health outcomes over a 12 wk period. Fifty-five overweight and/or obese participants (age (mean ± SEM): 26 ± 1; body mass index (BMI) (kg/m2): 30.5 ± 0.6) completed this double-blind, placebo-controlled clinical trial. Participants were randomized to 12 wks of daily consumption of multi-ingredient supplement (MIS; n = 28; containing 50 mg forskolin, 500 mg green coffee bean extract, 500 mg green tea extract, 500 mg beet root extract, 400 mg α-lipoic acid, 200 IU vitamin E, and 200 mg CoQ10) or control placebo (PLA, n = 27; containing microcrystalline cellulose) matched in appearance. The co-primary outcomes were bodyweight and fat mass (kg) changes. The secondary outcomes included other body composition measures, plasma markers of obesity, fatty liver disease biomarkers, resting energy metabolism, blood pressure, physical performance, and quality of life. The post-intervention differences between MIS and PLA were examined via ANCOVA which was adjusted for the respective pre-intervention variables. After adjustment for pre-intervention data, there was a significant difference in weight (p < 0.001) and fat mass (p < 0.001) post-intervention between the PLA and MIS treatment arms. Post-intervention weight and fat mass were significantly lower in MIS. Significant post-intervention differences corrected for baseline were found in markers of clinical biochemistry (AST, p = 0.017; ALT, p = 0.008), molecular metabolism (GDF15, p = 0.028), and extracellular vesicle-associated miRNA species miR-122 and miR-34a in MIS (p < 0.05). Following the 12 wks of MIS supplementation, weight and body composition significantly improved, concomitant with improvements in molecular markers of liver health and metabolism.

The probiotic effects of host-associated Bacillus velezensis in diets for hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂)

This study was to evaluate the potential of a host-associated Bacillus velezensis as a probiotic for hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂). Diets (B0 to B5) containing 0, 0.90 × 108, 0.80 × 109, 0.85 × 1010, 0.90 × 1011, 0.83 × 1012 CFU/kg B. velezensis YFI-E109 were fed to the fish with initial weight (3.07 ± 0.08 g) in a recirculating aquaculture system for six weeks with three replicates, respectively. Probiotic effects were analyzed based on growth, body composition, liver and gut morphology, gut microbiome, and liver metabolome. Analysis of the bacterial genome has shown that the most abundant genes in B. velezensis YFI-E109 were distributed in carbohydrate and amino acid metabolism. Fish in groups B3 and B4 had better growth performance, and higher intestinal amylase (AMS) and lipase (LPS) activities compared with other groups (P < 0.05). Fish in groups B0 and B5 showed significant liver damage, while this status improved in group B3. The liver malondialdehyde (MDA) content in group B3 was lower than that in other groups (P < 0.05). The abundance of Mycoplasma, Ralstonia and Acinetobacter was significantly reduced in B3 and B5 compared to B0. The amino acid and carbohydrate metabolism pathways were enriched in group B3 compared with group B0. In conclusion, dietary B. velezensis YFI-E109 supplementation has the potential to improve growth, liver metabolism, and liver and gut health, and reshape the gut microbiome of hybrid yellow catfish. Excessive B. velezensis YFI-E109 reduced the prebiotic effects. The recommended dietary supplementation of B. velezensis YFI-E109 is 0.31 × 1010 to 0.77 × 1011 CFU/kg for hybrid yellow catfish according to the quadratic regression method by plotting specific growth rate (SGR), feed conversion ratio (FCR), MDA and activities of AMS against dietary B. velezensis YFI-E109 levels.

Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway

BackgroundNon-alcoholic fatty liver disease (NAFLD) has been well defined as a common chronic liver metabolism disorder. Statins as a first-line therapeutic treatment had some side effects. Here, we found that Fumigaclavine C (FC) was collected from endophytic Aspergillus terreus via the root of Rhizophora stylosa (Rhizophoraceae), had potential anti-adipogenic and hepatoprotective effects both in vitro and in vivo without obvious adverse side effects. However, the mechanisms of the prevention and management of FC for hepatic steatosis are incompletely delineated.MethodsThe pharmacodynamic effects of FC were measured in high-fat diet (HFD)-induced obese mice. Liver index and blood biochemical were examined. Histopathological examination in the liver was performed by hematoxylin & eosin or oil red O. The levels of serum TG, TC, LDL-c, HDL-c, FFA, T-bili, ALT, AST, creatinine, and creatine kinase were estimated via diagnostic assay kits. The levels of hepatic lipid metabolism-related genes were detected via qRT-PCR. The expression levels of hepatic de novo lipogenesis were quantitated with Western blot analysis. ResultsFC-treatment markedly reduced hepatic lipid accumulation in HFD-induced obese mice. FC significantly attenuated the hepatic lipid metabolism and ameliorated liver injury without obvious adverse side effects. Moreover, FC also could dose-dependently modulate the expressions of lipid metabolism-related transcription genes. Mechanically, FC notably suppressed sterol response element binding protein-1c mediated de novo lipogenesis via interfering with the RhoA/ROCK signaling pathway by decreasing the levels of geranylgeranyl diphosphate and farnesyl diphosphate.ConclusionsThese findings suggested that FC could improve hepatic steatosis through inhibiting de novo lipogenesis via modulating the RhoA/ROCK signaling pathway.

Long-Term Dietary Fish Meal Substitution with the Black Soldier Fly Larval Meal Modifies the Caecal Microbiota and Microbial Pathway in Laying Hens.

Feeding laying hens with black soldier fly larval (BSFL) meal improves their performance. However, the beneficial mechanism of BSFL meals in improving the performance of laying hens remains unclear. This study investigated the effects of the BSFL diet on liver metabolism, gut physiology, and gut microbiota in laying hens. Eighty-seven Julia hens were randomly assigned to three groups based on their diets and fed maize grain-and soybean meal-based diets mixed with either 3% fish meal (control diet), 1.5% fish and 1.5% BSFL meals, or 3% BSFL meal for 52 weeks. No significant differences were observed in biochemical parameters, hepatic amino acid and saturated fatty acid contents, intestinal mucosal disaccharidase activity, and intestinal morphology between BSFL diet-fed and control diet-fed laying hens. However, the BSFL diet significantly increased the abundance of acetic and propionic acid-producing bacteria, caecal short-chain fatty acids, and modified the caecal microbial pathways that are associated with bile acid metabolism. These findings indicate that consuming a diet containing BSFL meal has minimal effects on plasma and liver nutritional metabolism in laying hens; however, it can alter the gut microbiota associated with short-chain fatty acid production as well as the microbial pathways involved in intestinal fat metabolism. In conclusion, this study provides evidence that BSFL can enhance enterocyte metabolism and gut homeostasis in laying hens.

Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 (Adgrf1).

Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism. We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively. These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1. This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.

Trehalose-induced SIRT1/AMPK activation regulates SREBP-1c/PPAR-α to alleviate lipid accumulation in aged liver.

Aging is associated with a disturbance in the regulation of the metabolic function of the liver, which increases the risk of liver and systemic diseases. Trehalose, a natural disaccharide, has been identified to reduce dyslipidemia, hepatic steatosis, and glucose intolerance. However, the roles of trehalose on lipid metabolism in aged liver are unclear which was investigated in this study. Thirty-two male Wistar rats were randomly allocated into four groups (n = 8). Two groups of aged (24months) and young (4months) rats were administered 2% trehalose solution orally for 30days. Control groups of aged and young rats did not receive any treatment. At the end of the treatment period, blood samples and liver tissues were collected. Then the expression of SIRT1, AMPK, SREBP-1c, and PPAR-α and the level of AMPK phosphorylation (p-AMPK) were quantified by real-time polymerase chain reaction and western blotting. Moreover, biochemical parameters and the histopathology of livers were evaluated. Trehalose supplementation increased the level of SIRT1, p-AMPK, and PPAR-α, whereas the level of SREBP-1c was diminished in the liver of old animals. In addition, treatment with trehalose improved histopathological features of senescent livers. Taken together, our results show that old rats developed lipogenesis in the liver which was alleviated with trehalose. Therefore, trehalose may be an effective intervention to reduce the progression of aging-induced liver diseases.

Transcriptome analysis of healthy and fatty liver revealed that inhibition of SLCO1B3 induces abnormal liver metabolism and lipid synthesis

The liver serves as the central organ for lipid metabolism, making it a crucial component of chicken physiology. However, the intricate regulation of lipid absorption, synthesis, decomposition, and transport within the liver is influenced by various factors, such as environmental conditions, diet, and genetics. Recent research has suggested that numerous functional genes and transcription factors play a pivotal role in liver metabolism via different molecular mechanisms. In this study, we examined the transcriptomes of both healthy and fatty chicken livers to better understand the role of functional genes in chicken liver fat metabolism. Our bioinformatics analysis of RNA-seq data revealed differential expression of SLCO1B3 in healthy liver and fatty liver, with lower ex-pression levels observed in fatty liver. To further investigate the potential role of SLCO1B3 in liver metabolism, we conducted in vitro experiments to knock down its expression in primary hepatocytes. Our results indicated that SLCO1B3 could suppress lipogenesis, hepatocyte apoptosis, and inflammation. These findings provide insight into the molecular mechanism of SLCO1B3 as a functional gene capable of regulating fat metabolism in chicken liver, and may contribute to ad-dressing the issue of fatty liver in chicken.

Plastic nanoparticles cause proteome stress and aggregation by compromising cellular protein homeostasis ex vivo and in vivo

Decomposition of plastic materials into minuscule particles and their long-term uptake pose increasing concerns on environmental sustainability and biosafety. Besides common cell viability and cytotoxicity evaluations, how plastic nanoparticles interfere with different stress response pathways and affect cellular fitness has been less explored. Here, we provided the first piece of evidence to demonstrate plastic nanoparticles potentially can deteriorate proteome stability, compromise cellular protein homeostasis, and consequently cause global proteome misfolding and aggregation. Polystyrene (PS) nanoparticles of different sizes and surface charges were exploited as model plastic materials. In cell lysate and human blood plasma, naked PS nanoparticles with hydrophobic surface deteriorated proteome thermodynamic stability and exaggerated its aggregation propensity. While no cell viability ablation was observed in cells treated with PS nanoparticles up to 200 μg·mL−1, global proteome aggregation and stress was detected by a selective proteome aggregation sensor. Further proteomics analysis revealed how protein homeostasis network was remodeled by positively charged PS nanoparticles via differential expression of key proteins to counteract proteome stress. In mice model, size-dependent liver accumulation of positively charged PS nanoparticles induced hepatocellular proteome aggregation and compromised protein homeostasis network capacity that were invisible to standard alanine transaminase and aspartate transaminase (ALT/AST) liver function as-say and histology. Meanwhile, long-term liver accumulation of plastic nanoparticles deteriorated liver metabolism and saturated liver detoxification capacity of overdosed acetaminophen. This work highlighted the impact of nanoplastics on cellular proteome integrity and cellular fitness that are invisible to current biochemical assays and clinical tests.

Sparassis latifolia Polysaccharide Attenuates Cholesterol in Rats Maintained on a High-Fat, High-Cholesterol Diet

Sparassis latifolia polysaccharide (SLP) has broad application prospects as a raw material of functional food. This study aimed to investigate the effects of SLP on liver cholesterol metabolism and its mechanism. Sprague–Dawley rats were fed a high-fat, high-cholesterol diet, and various assessments were conducted including hematoxylin and eosin staining, measurement of liver and metabolic indices, and antioxidant analysis. In addition, fluorescence quantitative reverse transcription-polymerase chain reaction was performed to analyze mRNA expression, and gas chromatography-mass spectrometry was employed for screening differential metabolites. The results demonstrated that SLP reduced the abnormal increase in the liver index caused by high fat and cholesterol and improved liver tissue morphology, metabolism level, and antioxidant-related enzyme activities. The polysaccharide regulated the liver sterol metabolism pathway, decreased the mRNA expression levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and sterol O-acyltransferase 1 (SOAT1), upregulated the mRNA expression levels of cholesterol 7α hydroxylase (CYP7α-1) and ABCA1, and increased the contents of propionic acid and butyric acid in the liver. These findings indicated a novel pathway through which SLP prevented hepatic lipid deposition and ameliorated sterol metabolism via regulating the HMG-CoAR-CYP7α-1 axis.

NcBAF enhances PXR-mediated transcriptional activation in the human and mouse liver

Pregnane X receptor (PXR) is one of the key regulators of drug metabolism, gluconeogenesis, and lipid synthesis in the human liver. Activation of PXR by drugs such as rifampicin, simvastatin, and efavirenz causes adverse reactions such as drug-drug interaction, hyperglycemia, and dyslipidemia. The inhibition of PXR activation has merit in preventing such adverse events. Here, we demonstrated that bromodomain containing protein 9 (BRD9), a component of non-canonical brahma-related gene 1-associated factor (ncBAF), one of the chromatin remodelers, interacts with PXR. Rifampicin-mediated induction of CYP3A4 expression was attenuated by iBRD9, an inhibitor of BRD9, in human primary hepatocytes and CYP3A/PXR-humanized mice, indicating that BRD9 enhances the transcriptional activation of PXR in vitro and in vivo. Chromatin immunoprecipitation assay reveled that iBRD9 treatment resulted in attenuation of the rifampicin-mediated binding of PXR to the CYP3A4 promoter region, suggesting that ncBAF functions to facilitate the binding of PXR to its response elements. Efavirenz-induced hepatic lipid accumulation was attenuated by iBRD9 in C57BL/6J mice, suggesting that the inhibition of BRD9 would be useful to reduce the risk of efavirenz-induced hepatic steatosis. Collectively, we found that inhibitors of BRD9, a component of ncBAF that plays a role in assisting transactivation by PXR, would be useful to reduce the risk of PXR-mediated adverse reactions.

Hepatic transcript profiling in beef cattle: Effects of rumen-protected niacin supplementation.

The objective of our study was to assess the effect of rumen-protected niacin supplementation on the transcriptome of liver tissue in growing Angus × Simmental steers and heifers through RNA-seq analysis. Consequently, we wanted to assess the known role of niacin in the physiological processes of vasodilation, detoxification, and immune function in beef hepatic tissue. Normal weaned calves (~8 months old) were provided either a control diet or a diet supplemented with rumen-protected niacin (6 g/hd/d) for a 30-day period, followed by a liver biopsy. We observed a significant list of changes at the transcriptome level due to rumen-protected niacin supplementation. Several metabolic pathways revealed potential positive effects to the animal's liver metabolism due to administration of rumen-protected niacin; for example, a decrease in lipolysis, apoptosis, inflammatory responses, atherosclerosis, oxidative stress, fibrosis, and vasodilation-related pathways. Therefore, results from our study showed that the liver transcriptional machinery switched several metabolic pathways to a condition that could potentially benefit the health status of animals supplemented with rumen-protected niacin. In conclusion, based on the results of our study, we can suggest the utilization of rumen-protected niacin supplementation as a nutritional strategy could improve the health status of growing beef cattle in different beef production stages, such as backgrounding operations or new arrivals to a feedlot.

Lactobacillus gasseri LA39 promotes hepatic primary bile acid biosynthesis and intestinal secondary bile acid biotransformation.

A growing body of evidence has linked the gut microbiota to liver metabolism. The manipulation of intestinal microflora has been considered as a promising avenue to promote liver health. However, the effects of Lactobacillus gasseri LA39, a potential probiotic, on liver metabolism remain unclear. Accumulating studies have investigated the proteomic profile for mining the host biological events affected by microbes, and used the germ-free (GF) mouse model to evaluate host-microbe interaction. Here, we explored the effects of L. gasseri LA39 gavage on the protein expression profiles of the liver of GF mice. Our results showed that a total of 128 proteins were upregulated, whereas a total of 123 proteins were downregulated by treatment with L. gasseri LA39. Further bioinformatics analyses suggested that the primary bile acid (BA) biosynthesis pathway in the liver was activated by L. gasseri LA39. Three differentially expressed proteins (cytochrome P450 family 27 subfamily A member 1 (CYP27A1), cytochrome P450 family 7 subfamily B member 1 (CYP7B1), and cytochrome P450 family 8 subfamily B member 1 (CYP8B1)) involved in the primary BA biosynthesis pathway were further validated by western blot assay. In addition, targeted metabolomic analyses demonstrated that serum and fecal β‍-muricholic acid (a primary BA), dehydrolithocholic acid (a secondary BA), and glycolithocholic acid-3-sulfate (a secondary BA) were significantly increased by L. gasseri LA39. Thus, our data revealed that L. gasseri LA39 activates the hepatic primary BA biosynthesis and promotes the intestinal secondary BA biotransformation. Based on these findings, we suggest that L. gasseri LA39 confers an important function in the gut‒liver axis through regulating BA metabolism.

Metabolic regulation of glucagon secretion.

Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.

Effects of a high-fat low-carbohydrate diet under different energy conditions on glucose homeostasis and fatty liver development in rats and on gluconeogenesis in the isolated perfused liver.

The beneficial effects of high-fat low-carbohydrate (HFLC) diets on glucose metabolism have been questioned and their effects on liver metabolism are not totally clear. The aim of this work was to investigate the effects of an HFLC diet under different energy conditions on glucose homeostasis, fatty liver development, and hepatic gluconeogenesis using the isolated perfused rat liver. HFLC diet (79% fat, 19% protein, and 2% carbohydrates in Kcal%) was administered to rats for 4 weeks under three conditions: ad libitum (hypercaloric), isocaloric, and hypocaloric (energy reduction of 20%). Fasting blood glucose levels and total fat in the liver were higher in all HFLC diet rats. Oral glucose tolerance was impaired in isocaloric and hypercaloric groups, although insulin sensitivity was not altered. HFLC diet also caused marked liver metabolic alterations: higher gluconeogenesis rate from lactate and a reduced capacity to metabolize alanine, the latter effect being more intense in the hypocaloric condition. Thus, even when HFLC diets are used for weight loss, our data imply that they can potentially cause harmful consequences for the liver.