Liver Lipid Metabolism Research Articles

Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators.

The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is on the rise and NAFLD is becoming the most common cause of chronic liver disease. In the USA, NAFLD affects over 30% of the population, with similar occurrence rates reported from Europe and Asia. This is due to the global increase in obesity and type 2 diabetes mellitus (T2DM) because patients with obesity and T2DM commonly have NAFLD, and patients with NAFLD are often obese and have T2DM with insulin resistance and dyslipidemia as well as hypertriglyceridemia. Excessive accumulation of triglycerides is a hallmark of NAFLD and NAFLD is now recognized as the liver disease component of metabolic syndrome. Liver glucose and lipid metabolisms are intertwined and carbon flux can be used to generate glucose or lipids; therefore, in this review we discuss the important transcription factors and coactivators that regulate glucose and lipid metabolism.

Hepatic Nampt Deficiency Aggravates Dyslipidemia and Fatty Liver in High Fat Diet Fed Mice.

Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.

Cotadutide effect in liver and adipose tissue in obese mice.

Obesity, adipose tissue inflammation, and nonalcoholic fatty liver disease (NAFLD) are associated with insulin resistance and type 2 diabetes (T2D). Cotadutide is a dual agonist GLP-1/glucagon, currently in a preclinical study phase 2 that presents an anti-obesity effect. Diet-induced obese (DIO) C57BL/6 mice were treated for 4 weeks with cotadutide (30 nm/kg once a day at 14:00 h). The study focused on epididymal white adipose tissue (eWAT), liver (NAFLD), inflammation, lipid metabolism, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathways, and the endoplasmic reticulum (ER) stress. As a result, cotadutide controlled weight gain, glucose intolerance, and insulin resistance and showed beneficial effects on plasma markers in DIO mice (triacylglycerol, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, leptin, adiponectin, monocyte chemoattractant protein-1, resistin, interleukin-6, tumor necrosis factor-alpha). Also, cotadutide lessened liver fat accumulation, eWAT proinflammatory markers, and ER stress. In addition, cotadutide improved lipid metabolism genes in eWAT, fatty acid synthase, peroxisome proliferator-activated receptor gamma and mitigates adipocyte hypertrophy and apoptosis. Furthermore, the effects of cotadutide were related to liver AMPK/mTOR pathway and ER stress. In conclusion, cotadutide induces weight loss and treats glucose intolerance and insulin resistance in DIO mice. In addition, cotadutide shows beneficial effects on liver lipid metabolism, mitigating steatosis, inflammation, and ER stress. Besides, in adipocytes, cotadutide decreases hypertrophy and reduces apoptosis. These actions rescuing the AMPK and mTOR pathway, improving lipid metabolism, and lessening NAFLD, inflammation, and ER stress in both eWAT and liver of DIO mice indicate cotadutide as a potentially new pharmacological treatment for T2D and associated obesity.

Chromium Nanoparticles Together with a Switch Away from High-Fat/Low-Fiber Dietary Habits Enhances the Pro-Healthy Regulation of Liver Lipid Metabolism and Inflammation in Obese Rats.

The study on Wistar rats was conducted to investigate the effects of a pharmacologically relevant dose 0.3 mg/kg body weight of chromium supplementation (commonly used picolinate or novel form as nanoparticles) and switching away from obesogenic dietary habits on the parameters of lipid metabolism, inflammation, and oxidative stress in liver and plasma. Favorable effects related to dietary changes from the obesogenic diet were considerably enhanced when the diet was supplemented with chromium nanoparticles. This combination exerted the strongest fat content and cholesterol reduction in the liver. Moreover, in this group, a favorable antioxidative effect was observed through GSH/GSSG elevation in the liver as well as ALT activity reduction in the plasma and IL-6 levels in the liver. The molecular mechanisms associated with regulating lipid metabolism, oxidative stress and inflammation might be related to lower expression of HIF-1α, COX-2, and LOX-1 and upregulation of PPARα in the liver. Supplementation with chromium nanoparticles without changes in the obesogenic diet also favorably affected lipid metabolism and oxidative stress in the liver; however, the examined effects were moderate. In conclusion, the favorable effects of switching from an obesogenic to a balanced diet on hepatic lipid metabolism, oxidative stress, and inflammation induced by an obesogenic diet might be enhanced by supplementation with chromium nanoparticles.

Pediococcus pentosaceus PR-1 modulates high-fat-died-induced alterations in gut microbiota, inflammation, and lipid metabolism in zebrafish.

Obesity is a health issue worldwide. This study aimed to evaluate the beneficial effects of Pediococcus pentococcus PR-1 on the modulating of gut microbiota, inflammation and lipid metabolism in high-fat-diet (HFD)-fed zebrafish. Adult zebrafish were fed a commercial (C), high fat (H, 25% fat), probiotic (P, 106 CFU/g), or high fat with probiotic (HP) diets twice daily for 5 weeks. Gut microbiota were analysed using 16S rRNA gene sequencing. Gene expressions of intestinal cytokine, intestinal TJ protein, and liver lipid metabolism were analysed by quantitative real-time polymerase chain reaction. Biochemical and histological analysis were also performed. P. pentosaceus PR-1 reduced body weight and BMI, indicating its anti-obesity effect. The 16S rRNA sequencing results showed HFD induced a distinct gut microbiota structure from C group, which was restored by probiotic. P. pentosaceus PR-1 improved gut health by decreasing the abundance of Ralstonia and Aeromonas which were increased induced by HFD. Moreover, probiotic restored abundance of Fusobacteria, Cetobacterium and Plesiomonas, which were decreased in HFD-fed zebrafish. The results of quantitative real-time polymerase chain reaction showed probiotic suppressed HFD-induced inflammation by decreasing the expressions of IL-1b and IL-6. Levels of hepatic TNF-α, IL-1ß, and IL-6 were reduced by probiotic in HFD-fed zebrafish. Probiotic also ameliorated gut barrier function by increasing the expressions of occludin, Claudin-1, and ZO-1. Probiotic exerted anti-adipogenic activity through regulating the expressions of SREBP1, FAS and LEPTIN. Levels of hepatic triglyceride, total cholesterol, low density lipoprotein were also reduced by probiotic. Histological analysis showed probiotic alleviated liver steatosis and injury induced by HFD. P. pentosaceus PR-1 might be useful as a dietary health supplement, especially for reducing obesity.

Pioglitazone can improve liver sex hormone-binding globulin levels and lipid metabolism in polycystic ovary syndrome by regulating hepatocyte nuclear factor-4α

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder that is closely correlated with insulin resistance. Sex hormone-binding globulin (SHBG) is an important carrier for regulating androgen activity and is affected by insulin level, which is related to metabolic abnormalities and long-term prognosis of PCOS. Insulin sensitizer pioglitazone can improve the SHBG level and dyslipidaemia in PCOS, but the mechanism remains unclear. We investigated liver SHBG expression, liver lipid levels, and the effects and potential mechanisms of pioglitazone on reproductive and metabolic disorders in a rat model of polycystic ovary syndrome with insulin resistance (PCOS-IR). PCOS-IR was induced by letrozole and a high-fat diet. Metformin was used as a positive control. Additionally, dihydrotestosterone and oleic acid combined with palmitic acid were used to induce the HepG2 cell models with IR. The cells were exposed to pioglitazone alone or in combination with a hepatocyte nuclear factor (HNF)− 4α inhibitor. Changes in biochemical characteristics were analysed using an enzyme-linked immunosorbent assay. Vaginal smears were used to analyse the oestrous cycle, and ovarian histology was used to analyse the changes in ovarian morphology. The degree of IR in vivo and in vitro was measured using the hyperinsulinaemic-euglycaemic clamp and glucose oxidase techniques. The levels of key anabolism-related proteins, including SHBG, HNF-4α, and peroxidase proliferator-activated receptor (PPAR-γ), were measured using western blots. Pioglitazone and metformin significantly increased the SHBG levels in the sera and livers. Compared to metformin, pioglitazone significantly improved the lipid droplet deposition, triglyceride (TG) and total cholesterol (TC) levels, HNF-4α protein expression, and weights of the livers in the PCOS-IR rats. After applying pioglitazone with an HNF-4α inhibitor in the PCOS-IR cell models, we found that pioglitazone may increase SHBG and improve IR, TG, and TC levels by upregulating HNF-4α. Similar to metformin, pioglitazone also restored the oestrous cycle and ovarian morphology, ameliorated IR and hyperandrogenaemia in the PCOS-IR rats. Our findings hint at the value of HNF-4α in the treatment of PCOS by PIO, which could shed light on potential targets that may be used in treatments for PCOS with metabolic disorders.

Eucommia ulmoides Oliver enhances the antioxidant capacity and protects Micropterus salmoides from liver damage and immune function impairment caused by a high starch diet

Eucommia ulmoides Oliver (EuO) is a traditional Chinese herb with effects on repairing disorders of liver lipid metabolism and enhancing immunity in mice. In this study, the effects of EuO on immune enhancement and liver protection of M. salmoides were tested by adding 3% EuO to a high-starch diet and were evaluated by histopathology, enzymology, flow cytometry, and molecular biology. The results showed that the high starch diet promoted hepatocytes apoptosis, damaged the liver, and led to impaired immune function. However, the integrality of liver was recoverd, innate response was enhanced, hepatocyte apoptosis was inhibited, and antioxidant capacity was improved after treatment with EuO. These findings reveal that EuO could improve the immune function while also repairing the M. salmoides liver injury induced by a high starch diet. This study provides a theoretical basis for EuO to solve the liver disease of M. salmoides caused by a high starch diet.

Hydroxysafflor yellow A regulates lymphangiogenesis and inflammation via the inhibition of PI3K on regulating AKT/mTOR and NF-κB pathway in macrophages to reduce atherosclerosis in ApoE-/- mice

BackgroundMacrophage-mediated inflammatory infiltration and pathological lymphangiogenesis around atherosclerotic plaques are newly highlighted treatment targets of atherosclerosis. Although the effect of Hydroxysafflor yellow A(HSYA) on atherosclerosis was clear, few studies focus on the regulation of HSYA on such mechanisms. PurposeThis study aimed to uncover the key site of HSYA on improving atherosclerosis by regulating macrophage-induced inflammation and lymphangiogenesis. Study designThis study was designed to explore the new mechanism of HSYA on alleviating atherosclerosis in vitro and in vivo. MethodsWe determined the expression of vascular endothelial growth factor C(VEGF-C) in Raw264.7 cells and high-fat diet fed ApoE knockout (ApoE−/−) mice. Raw264.7 cells were treated with HSYA under the stimulation of LPS and ox-LDL. HFD induced ApoE−/− mice were given different concentrations of HSYA-saline solution by tail vein injection and ATV-saline suspension by gavage. C57/B6j mice fed with chow diet were used for the control group. H&E, oil red O and immunofluorescence staining analysis were used for visualizing the pathological changes. The biological impact of HSYA was evaluated by body weight, lipid metabolism, inflammation levels, and corresponding function indexes of kidney and liver. RT-qPCR and western blot methods were conducted to determine the expression of the inflammation and lymphangiogenesis factors. Molecular docking and microscale thermophoresis analysis were used to verify the combination of HSYA and PI3K. ResultsIn vivo, HSYA reduced the plaque formation, hepatic steatosis and inflammation-related lymphangiogenesis (IAL). It also changed the serum levels of inflammation (VEGF-C, TNF-α, IL-6, VCAM1, MCP1), lipid indexes (LDL, CHOL, TRIG) and relevant lymphangiogenesis (VEGF-C and LYVE-1) and inflammation (VCAM-1 and IL-6) signals in the aorta. In vitro, HSYA regulated Akt/mTOR and NF-κB activation by the inhibition of PI3K in macrophages. ConclusionHSYA affects inflammation and inflammation-associated lymphangiogenesis via suppressing PI3K to affect AKT/mTOR and NF-B pathway activation in macrophages, showing a comprehensive protective effect on atherosclerosis.

Microbially produced vitamin B12 contributes to the lipid-lowering effect of silymarin

Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, we investigate the contributions of the gut microbiota to the improvement of liver lipid metabolism by silymarin. We find i) strong and significant microbial shifts upon silymarin but not silibinin treatment; ii) over 60% variations of liver fat are explained by silymarin-induced bacterial B12 production in male rats but not in male germ-free mice; iii) fecal microbiota transplantation confirms their protective roles against liver fat accumulation; iv) upregulation of one-carbon metabolism and fatty acid degradation pathways are observed based on the liver transcriptome analyses; and v) in humans the delta changes of serum B12 associate negatively with the fluctuations of serum triglycerides. Overall, we reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.

Lactobacillus Plantarum injection at the embryonic stage alters the early growth performance and lipid metabolism of broilers by specific genera of bacteria

The main objective of this study was to explore the effects of broiler embryonic injection of Lactobacillus Plantarum on the growth performance, lipid metabolism of serum and liver, microbial diversity, and short-chain fatty acids of broiler intestines after hatching. On d 14 of incubation, 720 eggs of Arbor Acres were randomly divided into 4 experimental groups: no treatment control (C), Treatments injected with stroke-physiological saline solution (S), Supernatant of MRS medium culture of lactobacillus (Q) and Lactobacillus Plantarum spp. (J). The Hatch rate for each replicate was counted at 1 d of age. After hatching, each group were divided into six replicates of 10 broilers, and chicken from groups C, Q and J were reared until 14 d of age. The production performance of the three groups of chicks from 1 to 14 days was recorded and statistically analyzed separately. Serum and liver tissue were collected at 7 and 14 days of age for the detection of lipid metabolism index. 16S rDNA sequencing and Short-Chain Fatty Acids measurement of cecum contents were performed at 14 days of age. Overall, Lactobacillus injection significantly reduced feed conversion ratio (FCR) at 1-7 and 1-14 days of age, compared to the other 2 groups (P < 0.05). 16S rRNA sequencing results showed that the Roseburia and coprobacillus had a significantly positive correlation with body weight (P < 0.05). The Roseburia and lachnospira were significantly correlated with FCR (P < 0.05), and the absolute abundance of g_Anaerostipes as a biomarker in the J group was higher than in the C group (P < 0.05). The Q and J group increased the content of acetic, propionic, butyric, and total acid in the cecum contents (P < 0.05). In the jejunum, the J group increased the content of acetic, propionic, butyric, and total acids compared to the C and Q groups (P < 0.05). The J group increased the blood of total cholesterol (TC) content at 1 day of age and the triglyceride (TG) content of 7- and 14-day-old broilers (P < 0.05). and the J group raised the TG, TC, and high-density lipoprotein (HDL) level in the liver of 14-day-old broilers (P < 0.05). The J group reduced the liver's low-density lipoprotein (LDL) at 14 days of age (P < 0.05). In conclusion, the lactobacillus Plantarum injection at the embryonic stage alters lipid metabolism by short-chain fatty acids especially butyric produced by the specific bacteria of Roseburia and Anaerostipes.

Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease.

NAFLD has become a major metabolic disease worldwide. A few studies have reported the potential relationship between mitochondrial pyruvate carrier 1 (MPC1) and inflammation, fibrosis, and insulin sensitivity in obese or NASH mouse models. However, the impact of MPC1 on NAFLD-related liver lipid metabolism and its role in the NAFLD progression require further investigation. MPC1 expression was measured in liver tissues from normal controls and patients with NAFLD. We characterized the metabolic phenotypes and expression of genes involved in hepatic lipid accumulation in MPC1 systemic heterozygous knockout (MPC1 +/- ) mice. Hepatic protein lactylation was detected using Tandem Mass Tags proteomics and verified by the overexpression of lactylation mutants in cells. Finally, the effect of MPC1 inhibition on liver inflammation was examined in mice and AML-12 cells. Here, we found that MPC1 expression was positively correlated to liver lipid deposition in patients with NAFLD. MPC1 +/- mice fed with high-fat diet had reduced hepatic lipid accumulation but no change in the expression of lipid synthesis-related genes. MPC1 knockout affected the lactylation of several proteins, especially fatty acid synthase, through the regulation of lactate levels in hepatocytes. Lactylation at the K673 site of fatty acid synthase inhibited fatty acid synthase activity, which mediated the downregulation of liver lipid accumulation by MPC1. Moreover, although MPC1 knockout caused lactate accumulation, inflammation level was controlled because of mitochondrial protection and macrophage polarization. In NAFLD, MPC1 levels are positively correlated with hepatic lipid deposition; the enhanced lactylation at fatty acid synthase K673 site may be a downstream mechanism.

Pregnancy Toxemia in Ewes: A Review of Molecular Metabolic Mechanisms and Management Strategies.

Pregnancy toxemia is a nutritional metabolic disease during late gestation in small ruminants. The condition is characterized by disorders in carbohydrate and fat metabolism. Obese and multiparous ewes are particularly susceptible to pregnancy toxemia, which may lead to maternal death, abortion, or premature birth. Highly productive multiparous meat ewes are major breeding animals, which has led to an increased incidence of the disease. However, the pathogenesis of pregnancy toxemia remains unclear and adequate disease prevention and treatment strategies are absent. Investigating the pathogenesis of pregnancy toxemia, especially the metabolic pathways of hepatic lipids, is key to an improved understanding of the condition. This review provides a snapshot of the genes that are associated with lipid metabolism in the ovine liver, including genes involved in fatty acid oxidation, acetyl coenzyme metabolism, and triglyceride synthesis; describes the interrelationships between these genes; and summarizes the diagnosis, prevention, and treatment of pregnancy toxemia.

Ginseng polysaccharides ameliorate abnormal lipid metabolism caused by acute alcoholic liver injury by promoting autophagy

AbstractThe study aimed to examine the effect of ginseng polysaccharide (GP) on acute alcoholic liver injury (AALI) and determine its underlying molecular mechanism. GP's in vitro and in vivo hepatoprotective effects were evaluated using LO2 cells and alcohol‐induced C57BL/6 male mice. Cell Counting Kit‐8, immunofluorescence, hematoxylin‐eosin, immunohistochemistry, and Western blot (WB) were used to detect alcohol‐induced lipid metabolism and autophagy levels in LO2 cells and liver. It was mainly composed of glucose, galactose, and arabinose in a molar ratio of 12.9:1.6:1.0. Experiments in vitro demonstrated that administration of GP to LO2 cells significantly increased the alcohol‐induced increase in cell viability. In addition, it can inhibit lipogenesis, enhance lipolysis, and stimulate autophagy. In alcohol‐induced mice, GP also inhibited hepatic histological lesions, prevented alanine aminotransferase and aspartate aminotransferase elevation, improved abnormal lipid metabolism, and boosted hepatocyte autophagy. In vivo and in vivo analysis of the underlying mechanisms revealed that GP promotes the expression of proteins in autophagy in AALI thereby alleviating it.

Effect of unsaturated fat and protein intake on liver fat in people at risk of unhealthy aging: 1-year results of a randomized controlled trial

BackgroundShort-term trials indicate improvement of intrahepatic lipids (IHLs) and metabolism by dietary protein or unsaturated fatty acids (UFAs) beyond weight loss. ObjectivesWe aimed to assess the effect of a dietary intervention high in protein and UFAs on IHLs and metabolic outcome after 12 mo, as long-term effects of such a combined intervention are unknown. MethodsWithin a 36-mo randomized controlled trial, eligible subjects (aged 50 to 80 y, ≥1 risk factor for unhealthy aging) were randomly assigned to either intervention group (IG) with high intake of mono-/poly-UFAs [15–20 percent of total energy (%E)/10%–15%E, respectively], plant protein (15%–25%E), and fiber (≥30 g/d), or control group [CG, usual care, dietary recommendations of the German Nutrition Society (fat 30%E/carbohydrates 55%E/protein 15%E)]. Stratification criteria were sex, known cardiovascular disease, heart failure, arterial hypertension, type 2 diabetes, and cognitive or physical impairment. Nutritional counseling and supplementation of foods mirroring the intended dietary pattern were performed in the IG. Diet-induced effects on IHLs, analyzed by magnetic resonance spectroscopy, as well as on lipid and glucose metabolism were predefined secondary endpoints. ResultsIHL content was analyzed in 346 subjects without significant alcohol consumption at baseline and in 258 subjects after 12 mo. Adjusted for weight loss, sex, and age, we observed a comparable decline of IHLs in IG and CG (−33.3%; 95% CI: −49.3, −12.3%; n = 128 compared with -21.8%; 95% CI: −39.7, 1.5%; n = 130; P = 0.179), an effect that became significant by comparing adherent IG subjects to adherent CG subjects (−42.1%; 95% CI: −58.1, −20.1%; n = 88 compared with -22.2%; 95% CI: −40.7, 2.0%; n = 121; P = 0.013). Compared with the CG, decline of LDL cholesterol (LDL-C) and total cholesterol (TC) was stronger in the IG (for LDL-C P = 0.019, for TC P = 0.010). Both groups decreased in triglycerides and insulin resistance (P for difference between groups P = 0.799 and P = 0.124, respectively). ConclusionsDiets enriched with protein and UFAs have beneficial long-term effects on liver fat and lipid metabolism in adherent older subjects.This study was registered at the German Clinical Trials Register, https://www.drks.de/drks_web/setLocale_EN.do, DRKS00010049. Am J Clin Nutr 20XX;xx:xx–xx.

Lipophagy: Molecular Mechanisms and Implications in Hepatic Lipid Metabolism.

The liver is the most significant metabolic organ in the body and plays an important role in lipid metabolism. Liver lipid metabolism disorders cause hepatic diseases such as hepatitis, hepatic cirrhosis, and hepatoma. Autophagy is a process of generating energy and building blocks by degrading redundant or damaged proteins and organelles. Thus, it helps in the maintenance of cellular homeostasis. Recent discoveries revealed that lipophagy plays a vital role in hepatic cellular homeostasis and lipid metabolism. Its imbalance is always associated with the perturbation of lipid metabolism in the liver. This article reviewed the molecular mechanisms involved in lipophagy and the interaction between lipophagy and hepatic lipid metabolism. Increasing evidence suggests that lipophagy is an effective method to resolve liver diseases.

BPA and its alternatives BPF and BPAF exaggerate hepatic lipid metabolism disorders in male mice fed a high fat diet

Alternatives to Bisphenol A (BPA), such as BPF and BPAF, have found increasing industrial applications. However, toxicological research on these BPA analogues remains limited. This study aimed to investigate the effects of BPA, BPF, and BPAF exposure on hepatotoxicity in mice fed with high-fat diets (HFD). Male mice were exposed to the bisphenols at a dose of 0.05 mg per kg body weight per day (mg/kg bw/day) for eight consecutive weeks, or 5 mg/kg bw/day for the first week followed by 0.05 mg/kg bw/day for seven weeks under HFD. The low dose (0.05 mg/kg bw/day) was corresponding to the tolerable daily intake (TDI) of BPA and the high dose (5 mg/kg bw/day) was corresponding to its no observed adverse effect level (NOAEL). Biochemical analysis revealed that exposure to these bisphenols resulted in liver damage. Metabolomics analysis showed disturbances of fatty acid and lipid metabolism in bisphenol-exposed mouse livers. BPF and BPAF exposure reduced lipid accumulation in HFD mouse liver by lowering glyceride and cholesterol levels. Transcriptomics analysis demonstrated that expression levels of genes related to fatty acid synthesis and metabolism were changed, which might be related to the activation of the PPAR signaling pathway. Besides, a feedback regulation mechanism might exist to maintain hepatic metabolic homeostasis. For the first time, this study demonstrated the effects of BPF and BPAF exposure in HFD-mouse liver. Considering the reality of the high prevalence of obesity nowadays and the ubiquitous environmental distribution of bisphenols, this study provides insight and highlights the adverse effects of BPA alternatives, further contributing to the consideration of the safe use of such compounds.

Ceruloplasmin-Deficient Mice Show Dysregulation of Lipid Metabolism in Liver and Adipose Tissue Reduced by a Protein Replacement

Ceruloplasmin is a ferroxidase that plays a role in iron homeostasis; its deficiency fosters inter alia iron accumulation in the liver, which expresses the soluble form of the protein secreted into the bloodstream. Ceruloplasmin is also secreted by the adipose tissue, but its role in adipocytes has been poorly investigated. We hypothesized that ceruloplasmin might have a role in iron/lipid interplay. We investigated iron/lipid dysmetabolism in the liver and adipose tissue of the ceruloplasmin-deficient mouse (CpKO) model of aceruloplasminemia and evaluated the effectiveness of ceruloplasmin replacement. We found that CpKO mice were overweight, showing adipose tissue accumulation, liver iron deposition and steatosis. In the adipose tissue of CpKO mice, iron homeostasis was not altered. Conversely, the levels of adiponectin and leptin adipokines behaved opposite to the wild-type. Increased macrophage infiltration was observed in adipose tissue and liver of CpKO mice, indicating tissue inflammation. The treatment of CpKO mice with ceruloplasmin limited liver iron accumulation and steatosis without normalizing the expression of iron homeostasis-related proteins. In the CpKO mice, the protein replacement limited macrophage infiltration in both adipose and hepatic tissues reduced the level of serum triglycerides, and partially recovered adipokines levels in the adipose tissue. These results underline the link between iron and lipid dysmetabolism in ceruloplasmin-deficient mice, suggesting that ceruloplasmin in adipose tissue has an anti-inflammatory role rather than a role in iron homeostasis. Furthermore, these data also indicate that ceruloplasmin replacement therapy may be effective at a systemic level.

More Than an Antioxidant: Role of Dietary Astaxanthin on Lipid and Glucose Metabolism in the Liver of Rainbow Trout (Oncorhynchus mykiss).

This study investigated the influence of dietary astaxanthin (AX) on glucose and lipid metabolism in rainbow trout liver. Two iso-nitrogenous and iso-lipidic diets were tested for 12 weeks in rainbow trout with an initial mean weight of 309 g. The S-ASTA diet was supplemented with 100 mg of synthetic AX per kg of feed, whereas the control diet (CTRL) had no AX. Fish fed the S-ASTA diet displayed lower neutral and higher polar lipids in the liver, associated with smaller hepatocytes and lower cytoplasm vacuolization. Dietary AX upregulated adipose triglyceride lipase (atgl), hormone-sensitive lipase (hsl2) and 1,2-diacylglycerol choline phosphotransferase (chpt), and downregulated diacylglycerol acyltransferase (dgat2), suggesting the AX's role in triacylglycerol (TAG) turnover and phospholipid (PL) synthesis. Dietary AX may also affect beta-oxidation with the upregulation of carnitine palmitoyltransferase 1 (cpt1α2). Although hepatic cholesterol levels were not affected, dietary AX increased gene expression of sterol regulatory element-binding protein 2 (srebp2). Dietary AX upregulated the expression of 6-phosphogluconate dehydrogenase (6pgdh) and downregulated pyruvate kinase (pkl). Overall, results suggest that dietary AX modulates the oxidative phase of the pentose phosphate pathway and the last step of glycolysis, affecting TAG turnover, β-oxidation, PL and cholesterol synthesis in rainbow trout liver.

Association Between Blood Calcium, Magnesium, and Non-alcoholic Fatty Liver Disease in Adults: a Cohort-Based Case-Control Study.

Previous studies have shown that calcium (Ca), magnesium (Mg), and Ca/Mg ratio are associated with inflammation and metabolic disorders, but their relationship with non-alcoholic fatty liver disease (NAFLD) is unclear. Thus, we aimed to explore the association between Ca, Mg, Ca/Mg ratio, and NAFLD in Chinese adults. We conducted a case-control study based on the Kailuan Cohort in China, including 1816 cases and 1111 gender- and age-matched controls. Dose-response relationships between blood Ca, Mg, Ca/Mg ratio, and NAFLD were evaluated using restricted cubic splines. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression models. A negative association between blood Ca (overall association P < 0.001 and linear association P < 0.001) and NAFLD as well as Ca/Mg ratio (overall association P = 0.002 and linear association P = 0.024) and NAFLD was observed. Compared with the highest quartile, the adjusted OR (95% CI) for the lowest quartile of Ca and Ca/Mg ratio was 2.116 (1.679-2.667) and 1.358 (1.076-1.713), respectively. A U-shaped relationship was found for blood Mg and NAFLD, with the highest OR of 1.685 in the lowest quartile group when using the second quartile as a reference. Additionally, we observed the interaction between alanine aminotransferase and blood Ca (P = 0.024), total cholesterol (P = 0.017), low-density lipoprotein-cholesterol (P = 0.013), and blood Mg, as well as total cholesterol and Ca/Mg ratio (P = 0.014). Lower blood Ca and Ca/Mg ratio were significantly associated with the risk of NAFLD. Liver function or lipid metabolism parameters may modify their association, suggesting an individualized prevention strategy for NAFLD.

Alleviation effect of conjugated linoleic acid on estradiol benzoate induced fatty liver hemorrhage syndrome in Hy-line male chickens.

The purpose of this study was to explore whether conjugated linoleic acid (CLA) could alleviate fatty liver hemorrhagic syndrome (FLHS) induced by estradiol benzoate intramuscular injection in laying hens. One hundred male Hy-Line white chickens were randomly divided into two groups, namely, the control (CON) and estradiol benzoate (E) groups, and both groups were fed the same basal diet. After injections of estradiol benzoate at 2 mg/kg every two days for a total of 7 times, chickens in the E group showed FLHS symptoms, including liver enlargement, hemorrhage, and steatosis. Then half of the chickens in the E group received an additional diet containing 5000 mg/kg CLA for 8 weeks. The results of morphological observations, hematoxylin and eosin staining, and Oil Red O staining showed that CLA alleviated liver enlargement, hemorrhage, and lipid accumulation in FLHS chickens. In addition, we measured liver function and lipid metabolism indicators, including ALT, AST, TG, TCH, HDL-C, and LDL-C, which further suggested that CLA mitigated the disturbance of serum and liver metabolism in FLHS chickens. Mechanistically, CLA inhibited hepatic de novo lipogenesis, cholesterol synthesis, and TG accumulation and increased TG hydrolysis in FLHS chickens by regulating the gene expression of CD36, ACC, FAS, SCD 1, DGAT2, LIPE, ATGL, CPT1A, SREBP-1c, SREBP-2, PPARγ, and PPARα. Furthermore, CLA ameliorated hepatic oxidative stress and inhibited NF-κB signaling pathway-mediated inflammation in FLHS chickens. In conclusion, CLA regulated lipid metabolism, thus further alleviating oxidative stress and inflammation to alleviate FLHS induced by estrogen in chickens.