High-fat Diet-induced Non-alcoholic Fatty Liver Research Articles

Therapeutic potential of Lactobacillus casei and Chlorella vulgaris in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD)-associated kidney damages: a stereological study.

The non-alcoholic fatty liver disease (NAFLD) is prevalent in as many as 25% of adults who are afflicted with metabolic syndrome. Oxidative stress plays a significant role in the pathophysiology of hepatic and renal injury associated with NAFLD. Therefore, probiotics such as Lactobacillus casei (LBC) and the microalga Chlorella vulgaris (CV) may be beneficial in alleviating kidney injury related to NAFLD. This animal study utilized 30 C57BL/6 mice, which were evenly distributed into five groups: the control group, the NAFLD group, the NAFLD + CV group, the NAFLD + LBC group, and the NAFLD + CV + LBC group. A high-fat diet (HFD) was administered to induce NAFLD for six weeks. The treatments with CV and LBC were continued for an additional 35 days. Biochemical parameters, total antioxidant capacity (TAC), and the expression of kidney damage marker genes (KIM 1 and NGAL) in serum and kidney tissue were determined, respectively. A stereological analysis was conducted to observe the structural changes in kidney tissues. A liver histopathological examination confirmed the successful induction of NAFLD. Biochemical investigations revealed that the NAFLD group exhibited increased ALT and AST levels, significantly reduced in the therapy groups (p < 0.001). The gene expression levels of KIM-1 and NGAL were elevated in NAFLD but were significantly reduced by CV and LBC therapies (p < 0.001). Stereological examinations revealed reduced kidney size, volume, and tissue composition in the NAFLD group, with significant improvements observed in the treated groups (p < 0.001). This study highlights the potential therapeutic efficacy of C. vulgaris and L. casei in mitigating kidney damage caused by NAFLD. These findings provide valuable insights for developing novel treatment approaches for managing NAFLD and its associated complications.

The therapeutic effect of alcoholic extract of Fumaria parviflora on high-fat diet-induced nonalcoholic fatty liver in rats: an animal experiment.

Nonalcoholic fatty liver disease (NAFLD) is a growing problem with a significant burden. Lifestyle modification is the recommended treatment, but researchers are exploring other options. This study focused on the effects of Fumaria parviflora (FP) extracts on NAFLD induced by a high-fat diet in rats. Thirty-five 10-week-old male Wister-Albino rats were divided into seven groups: normal diet control, high fat diet control, high fat diet with oral normal saline gavage, high fat diet with oral Atorvastatin gavage, and three groups receiving high fat diet with FP extract in 200mg/kg, 400mg/kg, and 700mg/kg.Blood samples of rats were used for the measurement of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).1×1cm Liver biopsies were taken, stained with Trichrome Stain (Masson) and Hematoxylin and eosin (H&E) stain for evaluation by a pathologist. Lab results showed that FP extract inhibits weight gain, has positive effects on triglyceride and alkaline phosphatase levels, and reduces hepatocyte ballooning and inflammation in rats. FP extract may lower liver enzymes and have a positive impact on triglyceride, LDL, and HDL levels in rats with NAFLD.

Identification of key genes involved in the alleviative effects of Polysaccharide of Atractylodes macrocephala Koidz on high-fat diet-induced nonalcoholic fatty liver disease in mice

Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent, but treatment options are limited. Previous studies have demonstrated the hepatoprotective effects of Polysaccharide of Atractylodes macrocephala Koidz (PAMK) against liver injury induced by various causes, but its potential in alleviating NAFLD remains unknown. This study aimed to investigate the potential of PAMK in improving NAFLD and its regulatory effects on gene transcription during the process. The results indicated that Highfatdiet (HFD) could induce NAFLD in mice, and PAMK was found to alleviate symptoms of NAFLD and mitigate liver injury caused by HFD. Transcriptome analysis revealed that PAMK affects both metabolic and inflammatory pathways, suggesting its dual impact on maintaining metabolic homeostasis and suppressing inflammation during NAFLD progression. The results of liver biochemical markers, key genes of the cholesterol pathway, glucose (GLU), and inflammatory factors further demonstrated the dual role of PAMK in metabolism and inflammation.

Would Combination Be Better: Swimming Exercise and Intermittent Fasting Improve High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Obese Rats via the miR-122-5p/SREBP-1c/CPT1A Pathway.

Swimming and intermittent fasting can both improve obesity-induced NAFLD, but which of the two is more effective and whether the combination of the two has a superimposed effect is inconclusive. The model of NAFLD in obese rats was established by a high-fat diet and performed swimming, intermittent fasting, and a combination of both interventions for 8 weeks. Serum lipids and enzyme activity were measured by an automatic biochemical analyzer. Liver morphostructural analysis was observed by transmission electron microscopy, and morphology was observed by HE staining. RT‒PCR was used to detect the mRNA level. Morphology and microstructure of the liver of model rats were impaired, with the upregulation of miR-122-5p, SREBP-1c, FASN and ACC1. Eight weeks of swimming exercise, intermittent fasting and the combination of both attenuate these effects, manifested by the downregulation of miR-122-5p and upregulation of CPT1A mRNA levels. There was no significant stacking effect of the combination of the swimming and intermittent fasting interventions. NAFLD leads to pathology in model rats. Eight weeks of swimming exercise, intermittent fasting and the combination of both can inhibit miR-122-5p and improve hepatic lipid metabolism, while no significant additive effects of combining the interventions were found.

Lipidomic Analysis of Liver and Adipose Tissue in a High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Mice Model Reveals Alterations in Lipid Metabolism by Weight Loss and Aerobic Exercise.

Detailed investigation of the lipidome remodeling upon normal weight conditions, obesity, or weight loss, as well as the influence of physical activity, can help to understand the mechanisms underlying dyslipidemia in metabolic conditions correlated to the emergence and progression of non-alcoholic fatty liver disease (NAFLD). C57BL/6 male mice were fed a normal diet (ND) or a high-fat diet (HFD) for 20 weeks. Subgroups within the high-fat diet (HFD) group underwent different interventions: some engaged in exercise (HFDex), others were subjected to weight loss (WL) by changing from the HFD to ND, and some underwent a combination of weight loss and exercise (WLex) during the final 8 weeks of the 20-week feeding period. To support our understanding, not only tissue-specific lipid remodeling mechanisms but also the cross-talk between different tissues and their impact on the systemic regulation of lipid metabolism are essential. Exercise and weight loss-induced specific adaptations in the liver and visceral adipose tissue lipidomes of mice were explored by the UPLC-TOF-MS/MS untargeted lipidomics methodology. Lipidomic signatures of ND and HFD-fed mice undergoing weight loss were compared with animals with and without physical exercise. Several lipid classes were identified as contributing factors in the discrimination of the groups by multivariate analysis models, such as glycerolipids, glycerophospholipids, sphingolipids, and fatty acids, with respect to liver samples, whereas triglycerides were the only lipid class identified in visceral adipose tissue. Lipids found to be dysregulated in HFD animals are related to well-established pathways involved in the biosynthesis of PC, PE, and TG metabolism. These show a reversing trend back to basic levels of ND when animals change to a normal diet after 12 weeks, whereas the impact of exercise, though in some cases it slightly enhances the reversing trend, is not clear.

Potential Hepatoprotective Effect of Matricaria Pubescens on High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Rats.

This study aimed to identify the phytochemical compounds of Matricaria pubescens by LC-MS/MS and evaluate the potential protective effect of its supplementation in high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in adult rats through modulation of oxidative stress and histopathological changes. Twenty-four male rats were randomly divided into four groups. The first group served as control and received the standard diet. The second group (HFD) received a high-fat diet only (30 % of sheep fat). The third group's (control+MP) animals received a standard diet supplemented with 5 % M. pubescens (w/w). The fourth group (HFD+MP) received a high-fat diet supplemented with 5 % M. pubescens for 16 weeks. LC-MS/MS analysis showed that M. pubescens contains many phytochemical compounds. It was observed that the ethanolic extract of M. pubescens has a higher phenolic content than the aqueous extract. The supplementation of M. pubescens (5 % w/w) to HFD rats decreased significantly (p<0.01) body weight, liver and epididymal adipose tissue relative weights, glycemia, triglycerides (TG), insulin resistance, liver markers, TNF-α, malondialdehyde (MDA), protein carbonyl (PCO), advanced oxidation protein products (AOPP) level, and increased reduced glutathione (GSH) level, glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase activities as well as ameliorated histological alterations through the reduction hepatic lipid deposition and adipocytes hypertrophy compared to the HFD group. We conclude that M. pubescens powder may be effective for correcting hyperglycemia, hypertriglyceridemia, insulin resistance, and liver markers while decreasing inflammation and oxidative stress in the liver of high-fat diet-fed rats.

Bacteroides fragilis aggravates high-fat diet-induced non-alcoholic fatty liver disease by regulating lipid metabolism and remodeling gut microbiota.

Gut microbiota dysbiosis is a prominent determinant that significantly contributes to the disruption of lipid metabolism. Consequently, it is essential to the occurrence and development of non-alcoholic fatty liver disease (NAFLD). Nevertheless, the connection between diet and symbiotic gut microbiota in the progression of NAFLD remains uncertain. The purpose of this study was to explore the role of supplementing commensal Bacteroides fragilis (B. fragilis) on lipid metabolism, gut microbiota, and metabolites in high-fat diet (HFD)-fed mice, elucidating the impact of gut microbiota and metabolites on the development of NAFLD. Our study revealed that supplementation with B. fragilis exacerbated both weight gain and obesity in mice. B. fragilis exacerbated blood glucose levels and liver dysfunction in mice. Furthermore, an increase in liver lipid accumulation and the upregulation of genes correlated with lipid metabolism were observed in mice. Under an HFD, supplementation of commensal B. fragilis resulted in alterations in the gut microbiota, notably a significant increase in Desulfovibrionaceae, which led to elevated endotoxin levels and thereby influenced the progression of NAFLD. It was interesting that the simultaneous examination of gut microbiota metabolites revealed a more pronounced impact of diet on short-chain fatty acids. This study represented the pioneering investigation into the impact of B. fragilis on NAFLD. Our findings demonstrated that B. fragilis induced dysregulation in the intestinal microbiota, leading to elevated levels of lipopolysaccharide and dysfunction in glucose and lipid metabolism, thereby exacerbating NAFLD.IMPORTANCESome intestinal symbiotic microbes are involved in the occurrence of the metabolic disorders. Our study investigated the impact of supplementing commensal Bacteroides fragilis on host metabolism in high-fat diet-fed mice. Research results indicated that adding a specific bacterial strain to the complex intestinal microecology can worsen metabolic conditions. This effect mainly affects the structural diversity of intestinal microorganisms, the increase in harmful bacteria in the gut, and the elevation of endotoxin levels, blood glucose, and lipid metabolism, thereby impacting the progression of non-alcoholic fatty liver disease (NAFLD). Understanding the principles that govern the establishment of microbial communities comprising multiple species is crucial for preventing or repairing dysfunctions in these communities, thereby enhancing host health and facilitating disease treatment. This study demonstrated that gut microbiota dysbiosis could contribute to metabolic dysfunction and provides new insights into how to promote gut microbiota in the prevention and therapy of NAFLD.

Exploring the Regulatory Effect of Tegillarca granosa Polysaccharide on High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice Based on Intestinal Flora.

To explore the potential mechanism of action of Tegillarca granosa polysaccharide (TGP) in treating nonalcoholic fatty liver disease (NAFLD), the study conducts in vivo experiments using male C57BL/6 mice fed a high-fat diet while administering TGP for 16 weeks. The study measures body weight, liver weight, serum biochemical markers, pathological histology, liver lipid accumulation, oxidative stress and inflammation-related factors, lipid synthesis and metabolism-related gene and protein expression, and the composition and abundance of intestinal flora. Additionally, short-chain fatty acid (SCFAs) content and the correlation between intestinal flora and environmental factors are measured. The results show that TGP effectively reduces excessive hepatic lipid accumulation, dyslipidemia, abnormal liver function, and steatosis in the mice with NAFLD. Moreover, TGP effectively regulates intestinal flora disorder, increases the diversity of intestinal flora, and affects the relative abundance of specific bacteria while also increasing the content of SCFAs. These findings provide a basis for exploring the regulatory effect of T. granosa polysaccharide on NAFLD based on intestinal flora and highlight its potential as a natural liver nutraceutical.

Ovothiol-A Mitigates High-Fat Diet-Induced Non-alcoholic Fatty Liver Disease in Rats

Background: Obesity is frequently linked to multiple comorbid and chronic illnesses, including non-alcoholic fatty liver disease, type 2 diabetes, cancer, and heart disease. Ovothiol-A is one of the most powerful natural antioxidants found in marine invertebrates like sea urchins. Objective: The current study aimed to investigate ovothiol-A's hypolipidemic and hypoglycemic potential in obese rats. Methods: All groups get a high-fat diet (HFD) for four weeks except for the control group. The control and HFD groups received distilled water, while the Ovothiol-A groups received two doses of Ovothiol-A (200 and 400 mg/kg orally) concurrent with HFD. Results: Weight gain, glucose, insulin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total cholesterol, triglycerides, low-density lipoprotein, malondialdehyde, and nitric oxide were all decreased after oral administration of Ovo at either the 200 or 400 mg/kg dose, while levels of high-density lipoprotein (HDL), glutathionereduced, catalase and glutathione-S-transferase increased. Histopathological alterations were less noticeable in the liver tissue of Ovothiol-A groups, with only a few vacuolated or pyknotic nuclei amongst a few dispersed hepatocytes. Conclusion: The current findings indicate that ovothiol-A protects against high-fat diet-induced fatty liver in rats. The anti-obesity mechanism of Ovothiol-A is associated with its hypolipidemic, hypoglycemic, and antioxidant properties.

Lauric acid attenuates hepato-metabolic complications and molecular alterations in high-fat diet-induced nonalcoholic fatty liver disease in rats

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver illness characterized by increase of lipid content in the liver. This study investigated the role of lauric acid to treat NAFLD in male adult Sprague Dawley rats. In this study, to induce NAFLD in the rats, a high-fat diet (HFD) was administered for eight consecutive weeks. Lauric acid groups received lauric acid (250 and 500 mg/kg; orally), concurrently with HFD for eight consecutive weeks. Lauric acid could ameliorate the serum levels of TG, TC, ALT, AST, blood glucose, and insulin. Moreover, lauric acid significantly elevated the levels of SOD, GSH, catalase, and IL-10. Additionally, it lowered the hepatic levels of MDA, ROS, MPO, 4-HNE, interleukin (IL)-1β, and tumor necrosis factor (TNF-α). Furthermore, lauric acid significantly up-regulated the hepatic expression of IRS1, AMPK, PI3K, and SIRT1 genes. In parallel, lauric acid could improve the histopathological picture of the liver and reduce the liver apoptosis via decreasing the expression of annexin V (Anx V). Finally, our data proposed that lauric acid could be an effective candidate for the NAFLD treatment.

Curcumin Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Endoplasmic Reticulum Stress in The Liver

Curcumin Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Endoplasmic Reticulum Stress in The Liver

Deletion of the PPARδ gene exacerbates high-fat diet-induced nonalcoholic fatty liver disease in mice through the gut-liver axis

Deletion of the PPARδ gene exacerbates high-fat diet-induced nonalcoholic fatty liver disease in mice through the gut-liver axis

Icariin alleviates high-fat diet-induced nonalcoholic fatty liver disease via up-regulating miR-206 to mediate NF-κB and MAPK pathways.

Nonalcoholic fatty liver disease (NAFLD) is an abnormal lipid accumulation disease in hepatocytes. The existing drugs for NAFLD have some side effects, so new therapeutic agents are required to be explored. In this study, the effect and mechanism of icariin (ICA) on high-fat diet-induced NAFLD were investigated. Firstly, a high-fat diet was used to construct a NAFLD rat model and HepG2 cells were treated with 1 mM free fatty acid (FFA). After ICA treatment, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured; liver injury and lipid deposition were observed by H&E and Oil Red O staining; interleukin-1β (IL-1β), IL-12, and IL-6 were measured by enzyme-linked immunosorbent assay. Additionally, qRT-PCR and western blot were performed to detect miR-206 expression and NF-κB/MAPK pathway-related protein expression in liver tissues and cells. After a variety of trials, we discovered that compared with the NAFLD group, ICA significantly reduced ALT, AST, TBil, TG, TC, and LDL-C levels and increased HDL-C levels, and improved liver tissue injury and lipid deposition. Moreover, ICA reduced IL-1β, IL-12, and IL-6 levels in liver tissues and cells as well as inhibited MAPK and NF-κB-related protein expression in the liver tissues. Notably, ICA could significantly increase miR-206 expression in liver tissues and cells. Further experiments confirmed that inhibition of miR-206 was able to reverse the effect of ICA on NAFLD. In conclusion, ICA can alleviate NAFLD by upregulating miR-206 to mediate NF-κB and MAPK pathways.

Akkermansia muciniphila and its outer membrane protein Amuc_1100 prevent high-fat diet-induced nonalcoholic fatty liver disease in mice

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. A. muciniphila and its outer membrane protein Amuc_1100 ameliorate metabolic disorders, enteritis, depression, and other diseases in mice. The NAFLD mouse model was established by feeding a high-fat diet (HFD) for 10 weeks. To assess the effect of A. muciniphila and Amuc_1100 on NAFLD, we used atorvastatin, a common lipid-lowering drug, as a positive control. A. muciniphila and Amuc_1100 significantly reduced body weight and serum ALT and AST levels, and improved serum lipid levels in NAFLD mice, which had similar effects to Ator. In addition, A. muciniphila and Amuc_1100 decreased the concentration of LPS in the serum and upregulated the mRNA expression of the colonic tight junction proteins. In the liver, A. muciniphila and Amuc_1100 significantly reduced the mRNA expression levels of nodular receptor protein 3 (NLRP3) and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB), and the protein and mRNA expression levels inflammatory cytokines. At the genus level, Amuc_1100 treatment significantly reduced the abundance of Coriobacteriaceae_UCG-002 produced by the HFD. The abundances of Blautia, norank_f__Ruminococcaceae, Lachnoclostridium, GCA-900066575 and Lachnospiraceae_UCG-006 increased dramatically. Together, A. muciniphila and Amuc_1100 alleviate HFD-induced NAFLD by acting on the gut-liver axis and regulating gut microbes.

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

Hepatic transcriptome delineates the therapeutic effects of Sanren Tang on high-fat diet-induced non-alcoholic fatty liver disease.

To evaluate the effects of Sanren Tang (SRT, ) on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice and to investigate the hepatic transcriptome regulated by SRT. The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry. The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks. Obeticholic acid was used as a control drug. Body weight, food intake, and homeostatic model assessment for insulin resistance (HOMA-IR) index were analysed. Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score (NAS). Serum alanine aminotransferase (ALT) and hepatic triglyceride (TG) levels were measured. Lipids in hepatocytes were visualised by Oil red staining. RNA-sequencing was performed to determine the transcriptome profile of the liver tissue. The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting. Four principal compounds were identified in the SRT: adenosine, amygdalin, luteoloside, and magnolol. SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice, and decreased HOMA-IR, NAS and ALT, and hepatic TG levels. Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously. Retinol metabolism, cytokine-cytokine receptor interaction, and peroxisome proliferator-activated receptor (PPAR) γ signalling were the top three SRT-regulated pathways in NAFLD. SRT significantly ameliorated HFD-induced NAFLD, which was correlated with the regulation of genes enriched in the retinol metabolism, cytokine-cytokine receptor interaction, and PPARγ signalling pathways.

Pomegranate-derived exosome-like nanovesicles ameliorate high-fat diet-induced nonalcoholic fatty liver disease via alleviating mitochondrial dysfunction

Plant-derived exosome-like nanovesicles carry a variety of bioactive substances and have multiple health benefits. Pomegranate (Punica granatum) is a popular fruit with hepatoprotective effects. However, the effects of pomegranate-derived exosome-like nanovesicles (PENs) on nonalcoholic fatty liver disease (NAFLD) are still unknown. Here, PENs were successfully isolated and characterized, and found to be internalized by HepG2 cells. Interestingly, PENs survived gastrointestinal environment and ameliorated lipid accumulation as well as mitochondrial dysfunction in palmitic acid (PA)-treated HepG2 cells. Importantly, oral administration of PENs accumulated in the liver of mice and effectively alleviated high-fat diet (HFD)-induced NAFLD by improving mitochondrial function, as evidenced by improvements of ATP content, mitochondrial complex I activity and oxidative stress. Moreover, PENs restored SIRT3/SOD2 signaling and improved SOD2 activity in the liver of HFD-fed mice. These findings provide new mechanistic insights into pomegranate’s hepatoprotection and demonstrate the therapeutic potential of PENs for NAFLD.

Intermittent fasting activates macrophage migration inhibitory factor and alleviates high-fat diet-induced nonalcoholic fatty liver disease

Switching to normal diet (ND) is the regular therapy for high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). Intermittent fasting (IF) is a unique treatment which may exhibits better therapeutic efficacy. Thus, we aim to investigate the therapeutic effects of these treatments and exploring the mechanisms. In the present study, NAFLD mouse model was induced by a 10-week HFD. Thereafter, mice adopted continued HFD, ND, or IF for the next 12 weeks. Finally, the liver was then harvested to assess lipid deposition, lipid metabolism, apoptosis, and autophagy, while blood was collected to determine blood glucose and insulin. The results showed that IF and ND treatment improved lipid deposition and metabolic disorder of NAFLD mice; the increasing body weight, liver weight, and HOMA-IR index of HFD mice were also alleviated by IF and ND. Furthermore, IF and ND treatment activated the macrophage migration inhibitory factor (MIF)/AMPK pathway and regulated its downstream autophagy and apoptosis. However, the efficacy of IF was better than ND. Both IF and ND activates MIF signaling and alleviate the lipotoxicity of NAFLD while IF therapy is more effective than ND. The different MIF up-regulation might be the underlying mechanism of why IF benefits more than ND.

Curcumin protects against high-fat diet-induced nonalcoholic simple fatty liver by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway in hamsters

Niemann-pick C1-like 1 (NPC1L1) mediates cholesterol absorption and plays a key role in the pathogenesis of nonalcoholic simple fatty liver (NASFL). Our previous study showed that curcumin reduced NPC1L1 expression and cholesterol absorption in Caco-2 cells. This study aimed to investigate whether curcumin could inhibit intestinal and hepatic NPC1L1 expression through suppressing sterol regulatory element binding protein-2 (SREBP-2) / hepatocyte nuclear factor 1α (HNF1α) pathway, then exert anti-NASFL effects. Six-week hamsters were fed high-fat diet (HFD) with or without 0.1% curcumin for 12 weeks. Curcumin supplementation lowered blood total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol levels (20.2%, 48.7%, and 36.5%), and reduced liver TC and TG contents (26.1% and 26.5%). Oil Red O staining demonstrated that curcumin significantly alleviated HFD-induced liver fat accumulation and hepatic steatosis, which was accompanied by reduced intestinal and hepatic NPC1L1, SREBP-2 and HNF1α expression (P < .05) and increased fecal neutral sterol excretion (114.5%). Furthermore, curcumin decreased cholesterol absorption in Caco-2 cells and HepG2 cells (49.2 % and 52.7 %). The inhibitory effects of curcumin on NPC1L1 expression and cholesterol absorption could be prevented by blockade of the SREBP-2 and HNF1α pathway. These findings indicated that curcumin protected against HFD-induced NASFL by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway, thus reducing intestinal cholesterol absorption and hepatic biliary cholesterol reabsorption, consequently alleviating liver cholesterol accumulation and steatosis. Our study provides evidence for curcumin as a potential nutritional therapy for NASFL by regulating NPC1L1 and enterohepatic circulation of cholesterol.

WED-414 - NAT10-mediated N4-acetylcytidine of hepatic lipogenesis-associated mRNA contributes to maternal high-fat diet-induced non-alcoholic fatty liver disease in juvenile offspring

WED-414 - NAT10-mediated N4-acetylcytidine of hepatic lipogenesis-associated mRNA contributes to maternal high-fat diet-induced non-alcoholic fatty liver disease in juvenile offspring