Lipid Accumulation In Liver Research Articles

Lactobacillus plantarum HF02 alleviates lipid accumulation and intestinal microbiota dysbiosis in high-fat diet-induced obese mice.

Obesity is closely associated with lipid accumulation and intestinal microbiota dysbiosis. It has been proved that probiotics supplement contributes to alleviate obesity. The objective of this study was to investigate the mechanism by which Lactobacillus plantarum HF02 (LP-HF02) alleviated lipid accumulation and intestinal microbiota dysbiosis in high-fat diet-induced obese mice. Our results showed that LP-HF02 ameliorated body weight, dyslipidemia, liver lipid accumulation, and liver injury in obese mice. As expected, LP-HF02 inhibited pancreatic lipase activity in small intestinal contents and increased fecal triglyceride levels, thereby reducing dietary fat hydrolysis and absorption. Moreover, LP-HF02 ameliorated the intestinal microbiota composition, as evidenced by the enhanced ratio of Bacteroides to Firmicutes, the decreased abundance of pathogenic bacteria (including Bacteroides, Alistipes, Blautia, and Colidextribacter) and the increased abundance of beneficial bacteria (including Muribaculaceae, Akkermansia, Faecalibaculum, and Rikenellaceae_RC9_gut_group). LP-HF02 also increased fecal short-chain fatty acids (SCFAs) levels and colonic mucosal thickness, and subsequently decreased serum lipopolysaccharide (LPS), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in obese mice. Additionally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot results demonstrated that LP-HF02 ameliorated hepatic lipid accumulation via activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. Therefore, our results indicated that LP-HF02 could be considered as a probiotic preparation for preventing obesity. © 2023 Society of Chemical Industry.

Sleeve Gastrectomy Improves Hepatic Glucose Metabolism by Downregulating FBXO2 and Activating the PI3K-AKT Pathway.

Type 2 diabetes mellitus (T2DM), a chronic metabolic disease, is a public health concern that seriously endangers human health. Sleeve gastrectomy (SG) can relieve T2DM by improving glucose homeostasis and enhancing insulin sensitivity. However, its specific underlying mechanism remains elusive. SG and sham surgery were performed on mice fed a high-fat diet (HFD) for 16 weeks. Lipid metabolism was evaluated via histology and serum lipid analysis. Glucose metabolism was evaluated using the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Compared with the sham group, the SG group displayed a reduction in liver lipid accumulation and glucose intolerance, and western blot analysis revealed that the AMPK and PI3K-AKT pathways were activated. Furthermore, transcription and translation levels of FBXO2 were reduced after SG. After liver-specific overexpression of FBXO2, the improvement in glucose metabolism observed following SG was blunted; however, the remission of fatty liver was not influenced by the over expression of FBXO2. Our study explores the mechanism of SG in relieving T2DM, indicating that FBXO2 is a noninvasive therapeutic target that warrants further investigation.

Bamboo shoot dietary fiber alleviates gut microbiota dysbiosis and modulates liver fatty acid metabolism in mice with high-fat diet-induced obesity.

Obesity is a common nutritional disorder characterized by an excessive fat accumulation. In view of the critical role of gut microbiota in the development of obesity and metabolic diseases, novel dietary therapies have been developed to manage obesity by targeting the gut microbiome. In this study, we investigated anti-obesity effects of bamboo shoot dietary fiber (BSDF) and the potential mechanisms. After 12 weeks of intervention with BSDF in high-fat mice, we detected obesity-related phenotypic indicators, and made transcriptomic analysis of liver tissue. Then we analyzed the changes of gut microbiota using 16S rRNA gene sequencing, explored the effect of BSDF on gut microbiota metabolites, and finally verified the importance of gut microbiota through antibiotic animal model. We found that BSDF was effective in reducing lipid accumulation in liver and adipose tissue and alleviating dyslipidemia and insulin resistance. Liver transcriptome analysis results showed that BSDF could improve lipid metabolism and liver injury by modulating peroxisome proliferator-activated receptor (PPAR) and fatty acid metabolic pathways. The 16S rRNA gene sequencing analysis of gut microbiota composition showed that BSDF significantly enriched beneficial bacteria such as Bifidobacterium, Akkermansia, Dubosiella, and Alloprevotella. Analysis of fecal metabolomics and gut microbiota metabolites revealed that BSDF increased the levels of several short-chain fatty acids and enriched bile acids, which may be important for improving lipid metabolism. Notably, the obesity-related metabolic disorders were abrogated after the abrogation of gut microbiota, suggesting that gut microbiota is a key factor in the beneficial effects of BSDF. Our study suggests that BSDF as a prebiotic supplement has the potential to improve obesity by improving gut microbiota and modulating host PPAR and fatty acid metabolic pathways.

Rapamycin suppresses inflammation and increases the interaction between p65 and IκBα in rapamycin-induced fatty livers.

Rapamycin treatment significantly increases lifespan and ameliorates several aging-related diseases in mice, making it a potential anti-aging drug. However, there are several obvious side effects of rapamycin, which may limit the broad applications of this drug. Lipid metabolism disorders such as fatty liver and hyperlipidemia are some of those unwanted side effects. Fatty liver is characterized as ectopic lipid accumulation in livers, which is usually accompanied by increased inflammation levels. Rapamycin is also a well-known anti-inflammation chemical. How rapamycin affects the inflammation level in rapamycin-induced fatty liver remains poorly understood. Here, we show that eight-day rapamycin treatment induced fatty liver and increased liver free fatty acid levels in mice, while the expression levels of inflammatory markers are even lower than those in the control mice. Mechanistically, the upstream of the pro-inflammatory pathway was activated in rapamycin-induced fatty livers, however, there is no increased NFκB nuclear translocation probably because the interaction between p65 and IκBα was enhanced by rapamycin treatment. The lipolysis pathway in the liver is also suppressed by rapamycin. Liver cirrhosis is an adverse consequence of fatty liver, while prolonged rapamycin treatment did not increase liver cirrhosis markers. Our results indicate that although fatty livers are induced by rapamycin, the fatty livers are not accompanied by increased inflammation levels, implying that rapamycin-induced fatty livers might not be as harmful as other types of fatty livers, such as high-fat diet and alcohol-induced fatty livers.

Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice

Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.

Liver fibrosis is a common pathological change in the liver of dairy cows with fatty liver

Fatty liver (i.e., hepatic lipidosis) is a prevalent metabolic disorder in dairy cows during the transition period, characterized by excess hepatic accumulation of triglyceride (TG), tissue dysfunction, and cell death. Detailed pathological changes, particularly hepatic fibrosis, during fatty liver remain to be determined. Liver fibrosis occurs as a consequence of liver damage, resulting from the excessive accumulation of extracellular matrix, which distorts the architecture of the normal liver, compromising its normal synthetic and metabolic functions. Thus, we aimed to investigate liver fibrosis status and its potential causal factors including oxidative stress, hepatocyte apoptosis, and production of inflammatory cytokines in the liver of cows with fatty liver. Forty-five dairy cows (parity, 3-5) were selected, and liver biopsy and blood were collected on the second week postpartum (days in milk, 10-14 d). On the basis of the degree of lipid accumulation in liver, selected cows were categorized into normal (n = 25; TG <1% wet wt), mild fatty liver (n = 15; 1% ≤ TG <5% wet wt), and moderate fatty liver (n = 5; 5% ≤ TG <10% wet wt). Compared with normal cows, blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, along with alanine aminotransferase and aspartate aminotransferase activities, were greater in the cows with fatty liver (mild and moderate). Hepatic extracellular matrix deposition, as indicated by Picrosirius red staining, was greater in cows with fatty liver than those with normal ones. In addition, we observed an increased proportion of collagen type I fiber in extracellular matrix with increased lipid accumulation in the liver. Compared with normal cows, the area of α-smooth muscle actin (α-SMA)-positive staining along with the mRNA abundance of collagen type I α 1 (COL1A1), ACTA2 (gene encoding α-SMA), and transforming growth factor-β (TGFB) were greater in cows with fatty liver. Compared with normal cows, hepatic contents of malondialdehyde, glutathione disulfide, and 8-isoprostane were greater, whereas total antioxidant capacity, the hepatic content of glutathione, and activities of antioxidant indicators, including superoxide dismutase, glutathione peroxidase, and catalase, were lower in cows with fatty liver. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and abundance of apoptosis-related molecules BAX, CASP3, CASP8, and CASP9 were greater in cows with fatty liver. However, mRNA abundance of the anti-apoptotic gene BCL2 did not differ. The mRNA abundance of pro-inflammatory cytokines including tumor necrosis factor-α (TNFA), interleukin-1β (IL1B), and interleukin-6 (IL6) was greater in the liver of cows with fatty liver. Overall, the present study indicated that fibrosis is a common pathological response to liver damage and is associated with oxidative stress, hepatocyte death, and inflammation.

Aging breaks liver vascular 'zone defense'.

Wang Lin and his colleagues explore how aging reprograms spatially unique pathways in liver endothelial cells to cause fibrosis. They find that loss of KIT in liver endothelial cells close to the central vein upregulates the chemokine receptor CXCR4 to stimulate inflammation, enhance fibrosis and increase lipid accumulation in aged liver.

Carnitine Supplementation Ameliorates the Steatosis and Ketosis Induced by Pivalate in Rats

These studies examined the effect in rats of carnitine supplementation on variables of fat metabolism altered by administration of sodium pivalate, a compound which induces a carnitine deficiency. Weanling male rats received 20 mmol/L sodium pivalate or 20 mmol/L sodium bicarbonate in their drinking water for 2 wk. They were food-deprived for 24 h, and to maximize fatty acid oxidation, were cold-stressed for 4 h. In Experiment 1, group 1 received the bicarbonate, group 2 received the pivalate, group 3 received the pivalate and 0.46 mmol L-carnitine in the diet/d, while group 4 received the pivalate and 0.95 mmol L-carnitine in the diet/d. In Experiment 2, group 1 received unsupplemented drinking water, group 2 received the bicarbonate, group 3 received the pivalate, and group 4 received the pivalate and 0.95 mmol L-carnitine in the diet/d. Pivalate-treated rats given the low carnitine diet had plasma and liver triglyceride levels (Experiment 1), plasma β-hydroxybutyrate concentrations (Experiments 1 and 2) and urinary dicarboxylic acid excretion (Experiment 2) significantly greater than those of controls (P < 0.05). The reduced tissue carnitine concentrations, starvation ketosis and lipid accumulation in the liver are findings also reported for human secondary carnitine deficiency due to organic acidurias. Supplementing the diet with L-carnitine at the level of 0.95 mmol/d significantly raised plasma and tissue carnitine concentrations and reduced the plasma β-hydroxybutyrate and liver triglyceride concentrations to levels not significantly different than control values. Carnitine supplementation ameliorates the degree of liver lipid accumulation and exaggerated starvation ketosis induced by pivalate.

4-PBA inhibits hypoxia-induced lipolysis in rat adipose tissue and lipid accumulation in the liver through regulating ER stress.

High-altitude hypoxia may disturb the metabolic modulation and function of both adipose tissue and liver. The endoplasmic reticulum (ER) is a crucial organelle in lipid metabolism and ER stress is closely correlated with lipid metabolism dysfunction. The aim of this study is to elucidate whether the inhibition of ER stress could alleviate hypoxia-induced white adipose tissue (WAT) lipolysis and liver lipid accumulation-mediated hepatic injury. A rat model of high-altitude hypoxia (5500 m) was established using hypobaric chamber. The response of ER stress and lipolysis-related pathways were analyzed in WAT under hypoxia exposure with or without 4-phenylbutyric acid (PBA) treatment. Liver lipid accumulation, liver injury, and apoptosis were evaluated. Hypoxia evoked significant ER stress in WAT, evidenced by increased GRP78, CHOP, and phosphorylation of IRE1α, PERK. Moreover, Lipolysis in perirenal WAT significantly increased under hypoxia, accompanied with increased phosphorylation of hormone-sensitive lipase (HSL) and perilipin. Treatment with 4-PBA, inhibitor of ER stress, effectively attenuated hypoxia-induced lipolysis via cAMP-PKA-HSL/perilipin pathway. In addition, 4-PBA treatment significantly inhibited the increase in fatty acid transporters (CD36, FABP1, FABP4) and ameliorated liver FFA accumulation. 4-PBA treatment significantly attenuated liver injury and apoptosis, which is likely resulting from decreased liver lipid accumulation. Our results highlight the importance of ER stress in hypoxia-induced WAT lipolysis and liver lipid accumulation.

Lambda-cyhalothrin induces lipid accumulation in mouse liver is associated with AMPK inactivation.

Lambda-cyhalothrin (LCT) is a critical synthetic Type II pyrethroid insecticide widely applied. Several studies suggest pyrethroids could induce fat accumulation, promote adipogenesis, and impair liver function. Now, the influences of LCT on the hepatic lipid metabolism and the cellular mechanism is still unknown. AMPK has important function in regulating cellular energy balance. To indicate the potential pathogenesis of liver injury caused by LCT exposure, ICR mice were orally administrated with LCT at a dose of 0.4mg/kg and 2mg/kg. The results suggest that LCT induced obesity, dyslipidemia and hepatic steatosis. In addition, LCT also induced oxidative stress, liver function injury, and disorganized structure of the liver. Furthermore, upregulation of PPARγ, FASN, and SREBP1c expression, as well as reduction of PPARα and FGF21 expression, bringing with decreases of phosphorylated ratios of AMPK and ACC were found in LCT-L group. These results indicate that LCT at 0.4mg/kg could result in dyslipidemia and hepatic steatosis in mice. In addition, activation of AMPK in hepatocytes effectively attenuated the effects of LCT. The detailed mechanism of LCT-induced hepatic steatosis is associated with AMPK and its downsteam genes. Activation of AMPK might be a novel protection against the progression of hepatic steatosis induced by LCT.

Assessment of nonalcoholic fatty liver function by photoacoustic imaging

SignificanceThe assessment of liver function plays an important role in the diagnosis of nonalcoholic fatty liver disease (NAFLD). Current noninvasive imaging methods have limited applicability in this regard.AimWe report an application of multispectral photoacoustic imaging (PAI), an emerging modality, to visualize lipid accumulation and liver function in NAFLD.ApproachWe first demonstrated the liver function reserve with indocyanine green (ICG) to verify the organ’s dysfunction due to NAFLD in a rabbit model. We then noninvasively quantified lipid content in the liver using multispectral PAI. The in vivo PAI results were compared and verified with photoacoustic ex vivo images and liver biopsy.ResultsA significant difference in the lipidmean value was observed [lipidmean = 0.081 ± 0.0161 arbitrary units (a.u.) control versus NAFLD 0.198 ± 0.048 a.u., P = 0.003]. Similar to in vivo analysis, a significant difference in lipidmean was observed (lipidmean = 0.0673 ± 0.0165 versus 0.486 ± 0.073 a.u., P < 0.0001) between control and NAFLD group ex vivo. For liver function, the control group showed a rapid decrease after the peak point, whereas the elimination of ICG for the NAFLD group was slower.ConclusionsOur study shows that PAI has the potential to provide a noninvasive biomarker for the assessment of liver function and lipid accumulation for NAFLD diagnosis and treatment.

The intervention effects of konjac glucomannan with different molecular weights on high-fat and high-fructose diet-fed obese mice based on the regulation of gut microbiota

Konjac is a high-quality dietary fiber rich in β-glucomannan, which has been reported to possess anti-obesity effects. To explore the effective components and the structure–activity relationships of konjac glucomannan (KGM), three different molecular weight components (KGM-1 (90 kDa), KGM-2 (5 kDa), KGM-3 (1 kDa)) were obtained, and systematical comparisons of their effects on high-fat and high-fructose diet (HFFD)-induced obese mice were investigated in the present study. Our results indicated that KGM-1, with its larger molecular weight, reduced mouse body weight and improved their insulin resistance status. KGM-1 markedly inhibited lipid accumulation in mouse livers induced by HFFD by downregulating Pparg expression and upregulating Hsl and Cpt1 expressions. Further investigation revealed that dietary supplementation with konjac glucomannan at different molecular weights caused β-diversity changes in gut microbes. The potential weight loss effect of KGM-1 maybe attributed to the abundance of changes in Coprobacter, Streptococcus, Clostridium IV, and Parasutterella. The results provide a scientific basis for the in-depth development and utilization of konjac resources.

Torularhodin-Loaded Bilosomes Ameliorate Lipid Accumulation and Amino Acid Metabolism in Hypercholesterolemic Mice.

Hypercholesterolemia is a cause of cardiovascular disease. Torularhodin is a carotenoid, and its entrapment in bilosomes helps to improve its bioavailability. The effects of torularhodin-loaded bilosomes on lipid accumulation, inflammatory response, and serum metabolic profiles in hypercholesterolemic ApoE-/- C57BL/6J mice were investigated by feeding a high-fat, high-cholesterol diet (HFHCD) for 20 weeks. At the same time, mice were gavaged with torularhodin-loaded bilosomes for 10 weeks. The results showed that torularhodin successfully alleviated weight gain and insulin resistance in mice and could also lower blood lipids. Meanwhile, torularhodin improved liver lipid accumulation in mice and modulated inflammatory factors in the "blood-liver-ileum." Nontargeted metabolomics revealed that torularhodin significantly increased the concentrations of l-tryptophan, glyceraldehyde, hypotaurine, pyrophosphate, and niacinamide in serum (p < 0.01). In addition, targeted amino acid metabolomics verification found that torularhodin promoted the metabolism of serum amino acids in mice, particularly for branched-chain amino acids, thereby helping to improve hypercholesterolemia in mice. Finally, interaction network bioinformatics was used to demonstrate that amino acid metabolism represented an important mechanism by which torularhodin improves lipid accumulation and inflammatory response in mice. Torularhodin can improve hypercholesterolemia in HFHCD-fed mice, thereby supporting the feasibility of its usage in food applications for cardiovascular disease prevention.

Protective Effects of Lactobacillus gasseri against High-Cholesterol Diet-Induced Fatty Liver and Regulation of Host Gene Expression Profiles.

Fatty liver is one of the most pervasive liver diseases worldwide. Probiotics play an important role in the progression of liver disease, but their effects on host regulation are poorly understood. This study investigated the protective effects of lactobacillus gasseri (L. gasseri) against high-cholesterol diet (HCD)-induced fatty liver injury using a zebrafish larvae model. Liver pathology, lipid accumulation, oxidative stress and hepatic inflammation were evaluated to demonstrate the changes in a spectrum of hepatic injury. Moreover, multiple indexes on host gene expression profiles were comprehensively characterized by RNA screening. The results showed that treatment with L. gasseri ameliorated HCD-induced morphological and histological alterations, lipid regulations, oxidative stress and macrophage aggregation in the liver of zebrafish larvae. Furthermore, the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that the core pathways of L. gasseri regulation were interleukin-17 (IL-17) signaling, phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, the regulation of lipolysis and adipocytes and fatty acid elongation and estrogen signaling. The genes at key junction nodes, hsp90aa1.1, kyat3, hsd17b7, irs2a, myl9b, ptgs2b, cdk21 and papss2a were significantly regulated by L. gasseri administration. To conclude, the current research extends our understanding of the protective effects of L. gasseri against fatty liver and provides potential therapeutic options for fatty liver treatment.

Qingrequzhuo capsule alleviated methionine and choline deficient diet-induced nonalcoholic steatohepatitis in mice through regulating gut microbiota, enhancing gut tight junction and inhibiting the activation of TLR4/NF-κB signaling pathway.

Qingrequzhuo capsule (QRQZ), composed of Morus alba L., Coptis chinensis Franch., Anemarrhena asphodeloides Bunge, Alisma plantago-aquatica subsp. orientale (Sam.) Sam., Citrus × aurantium L., Carthamus tinctorius L., Rheum palmatum L., Smilax glabra Roxb., Dioscorea oppositifolia L., Cyathula officinalis K.C.Kuan, has been used to treat nonalcoholic steatohepatitis (NASH) in clinic. However, the mechanism of QRQZ on NASH remains unclear. Recent studies have found that the dysfunction of gut microbiota could impair the gut barrier and induce the activation of TLR4/NF-kB signaling pathway, and further contribute to the inflammatory response in NASH. Modulating the gut microbiota to reduce inflammation could prevent the progression of NASH. In this study, a mouse model of NASH was generated by methionine and choline deficient diet (MCD) and treated with QRQZ. First, we evaluated the therapeutic effects of QRQZ on liver injury and inflammation in the NASH mice. Second, the changes in the gut microbiota diversity and abundance in each group of mice were measured through 16S rRNA sequencing. Finally, the effects of QRQZ on gut mucosal permeability, endotoxemia, and liver TLR4/NF-kB signaling pathway levels were examined. Our results showed that QRQZ significantly reduced the lipid accumulation in liver and the liver injury in NASH mice. In addition, QRQZ treatment decreased the levels of inflammatory cytokines in liver. 16S rRNA sequencing showed that QRQZ affected the diversity of gut microbiota and a f f e c t e d t h e r e l a t i v e a b u n d a n c e s o f D u b o s i e l l a , Lachnospiraceae_NK4A136_group, and Blautiain NASH mice. Besides, QRQZ could increase the expression of tight junction proteins (zonula occludens-1 and occludin) in gut and decrease the lipopolysaccharide (LPS) level in serum. Western blot results also showed that QRQZ treatment decreased the protein expression ofTLR4, MyD88 and the phosphorylation of IkB and NF-kBp65 and qPCR results showed that QRQZ treatment down-regulated the gene expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a in liver. In conclusion, our study demonstrated that QRQZ could reduce the lipid accumulation and inflammatory response in NASH model mice. The mechanisms of QRQZ on NASH were associated with modulating gut microbiota, thereby inducing the tight junction of gut barrier, reducing the endotoxemia and inhibiting the activation of TLR4/NFkB signaling pathway in liver.

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.

6-gingerol ameliorates weight gain and insulin resistance in metabolic syndrome rats by regulating adipocytokines

Metabolic syndrome (MetS) can lead to increase of insulin resistance (IR) and visceral adipose tissue production of adipocytokines. 6-gingerol is known to have antioxidant and anti-inflammatory activities. Aim of this study is to investigate the effects of 6-gingerol on high-fat high-fructose (HFHF) diet-induced weight gain and IR in rats through modulation of adipocytokines. To induce MetS, male Sprague-Dawley rats were fed with a HFHF diet for 16 weeks and at Week 8, single-dose low-dose streptozotocin (22 mg/kg) were intraperitoneally injected. After 8 weeks of HFHF diet feeding, the rats were treated orally with 6-gingerol (50, 100, and 200 mg/kg/day) once daily for 8 weeks. At the end of the study, all animals were terminated, serum, liver, and visceral adipose tissues were harvested for biochemical analysis including the measurements of total cholesterol, triglycerides, HDL-cholesterol, fasting plasma glucose, insulin, leptin, adiponectin, proinflammatory cytokines (TNF-α and IL-6) and liver and adipose tissue histopathology. Biochemical parameters namely serum total cholesterol (243.7 ± 127.6 vs 72.6 ± 3 mg/dL), triglycerides (469.2 ± 164.9 vs 49.3 ± 6.3 mg/dL), fasting plasma glucose (334 ± 49.5 vs 121 ± 8.5 mg/dL), HOMA-IR (0.70 ± 0.24 vs 0.32 ± 0.06), and leptin (6.19 ± 1.24 vs 3.45 ± 0.33 ng/mL) were significantly enhanced, whereas HDL-cholesterol (26.2 ± 5.2 vs 27.9 ± 1.1 mg/dL) and adiponectin level (14.4 ± 5.5 vs 52.8 ± 10.7 ng/mL) were lowered in MetS vs normal control. Moreover, MetS were marked a significant increase in body weight and proinflammatory cytokines. Treatment with 6-gingerol dose-dependently restored all of those alterations towards normal values as well as the accumulation of lipid in liver and adipose tissues. These findings demonstrate that 6-gingerol, in a dose-dependent mode, showed capability of improving weight gain and IR in MetS rats through modulation of adipocytokines.

Integrative analysis of transcriptome and lipidome reveals fructose pro-steatosis mechanism in goose fatty liver.

To further explore the fructose pro-steatosis mechanism, we performed an integrative analysis of liver transcriptome and lipidome as well as peripheral adipose tissues transcriptome analysis using samples collected from geese overfed with maize flour (control group) and geese overfed with maize flour supplemented with 10% fructose (treatment group). Overfeeding period of the treatment group was significantly shorter than that of the control group (p < 0.05). Dietary supplementation with 10% fructose induced more severe steatosis in goose liver. Compared with the control group, the treatment group had lower in ceramide levels (p < 0.05). The key differentially expressed genes (DEGs) (control group vs. treatment group) involved in liver fatty acid biosynthesis and steroid biosynthesis were downregulated. The conjoint analysis between DEGs and different lipids showed that fatty acid biosynthesis and steroid biosynthesis were the highest impact score pathways. In conclusion, fructose expedites goose liver lipid accumulation maximization during overfeeding.

(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet-Induced Hepatic Steatosis.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD.

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.