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

Regular moderate aerobic exercise improves high-fat diet-induced nonalcoholic fatty liver disease via monoacylglycerol O-acyltransferase 1 pathway suppression

PurposeMonoacylglycerol O-acyltransferase 1 (MGAT1) is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease (NAFLD). Thus, this study investigated the effect of exercise on suppression of the MGAT1 pathway in NAFLD tissue of high-fat diet (HFD)-induced obese rats. MethodsMale Sprague-Dawley rats were fed an HFD containing 45% fat for 6 weeks. Upon confirmation that NAFLD had been induced in the obese animals, they were divided into HFD-fed groups provided with exercise (HFD + EXE) or without exercise (HFD) and a group given dietary adjustment (DA) only, for a further 6 weeks of intervention treatment. The 6-week regular moderate aerobic exercise consisted of an accommodation phase with increasing exercise. Lipid accumulation in the liver tissue was determined by Oil Red O staining. The MGAT1 and liver lipogenic gene mRNA levels were measured by qPCR, and their protein levels by western blot assay. ResultsOil Red O staining showed that NAFLD was successfully induced by HFD-fed. The gene expression of MGAT1 was significantly lower in HFD + EXE than HFD. However, there was no significant difference between HFD + EXE and DA. The protein expression of MGAT1 was significantly lower in HFD + EXE than both HFD and DA. Messenger RNA and protein expression of other lipogenic genes were not different among groups. These data indicate that exercise suppresses MGAT1 pathway regardless of HFD feeding; in part, this effect could be greater than DA. ConclusionOur data suggest that exercise can improve NAFLD, which is probably due to suppression of MGAT1 pathway.

Therapeutic effects of Spirulina against experimentally-induced non-alcoholic fatty liver in rats may involve miR-21, -34a and -122

The present study was aimed to investigate the therapeutic effects of Spirulina against a rat model of high-fat-diet-induced non-alcoholic fatty liver (HFD-NAFL). The expression of mature miR-21, miR-34a and miR-122 and their targets genes; HPB1, SIRT1, and SREBP-1c; respectively were investigated as a molecular target of Spirulina. Fifty male rats were classified into two groups; negative control group (n = 10) and NAFL group (n = 40) which has been subdivided into 4 subgroups (10 rats each). One group is the untreated NAFL animals, while the other three groups were treated by oral aqueous Spirulina in a dose of 100, 200 and 500 mg/kg for 30 days. Serum AST, ALT, fasting glucose, and insulin were determined. The homeostasis model assessment index for insulin resistance (HOMA-IR) was calculated. Also, the hepatic expression of miR-21, miR-34a and miR-122 and their targets genes; HPB1, SIRT1, and SREBP-1c were assessed using real-time PCR.The NAFL animals showed marked induction of the hepatic expression of miR-21 and -34a which associated with marked suppression of their target genes; HPB1 and SIRT1; respectively. On the other hand, the expression of miR-122 showed significant suppression, while its target gene; SREBP-1c was greatly induced. The NAFL rats treated orally with different doses of Spirulina daily showed dose dependent ameliorations in body weight, liver functions, fasting blood sugar, insulin and HOMA-IR significantly. Spirulina treatment significantly and dose dependently modulate the hepatic expression of miR-21, miR-34a and miR-122 and their targets genes; HPB1, SIRT1, and SREBP-1c; respectively.Conclusion: Spirulina treatment of HFD-NAFL in rats modulated glucose, insulin sensitivity and showed anti-steatotic properties; effects that could be attributed at least partially to modulating hepatic microRNA expression. In conclusion, Spirulina can be considered as a potential anti-steatotic agent and might provide promising therapeutic approaches in NAFLD.

Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system

BackgroundNonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD.MethodsMale Sprague–Dawley rat offspring were placed in five experimental groups (n = 10–12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120.ResultsWe found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group.ConclusionOur results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.

Neonatal overfeeding induced glucocorticoid overexposure accelerates hepatic lipogenesis in male rats

BackgroundPostnatal overfeeding activates tissue glucocorticoid (GC) activity by up-regulating 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and increasing sensitivity to high-fat (HF) diet-induced non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate the effects of postnatal overfeeding on GC regulation and lipogenesis in the liver and to observe the impact of GC on hepatocyte lipid metabolism.MethodsIn vivo, Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3 and then given standard chow from postnatal week 3 (W3) to W13. In vitro, HepG2 cells were stimulated by GC, mifepristone (Mi) or GC + Mi within 48 h, followed by sodium oleate (OA) intervention (or not) for 24 h. Intracellular lipid droplets, triglyceride (TG) concentrations and gene expression related to lipid metabolism were measured in hepatic tissues or HepG2 cells.ResultsIn vivo, weight gain in the body and liver and TG concentrations in the liver were significantly increased in the SL rats compared to the NL rats at W3 and W13 (p < 0.05); mRNA expression of hepatic 11β-HSD1, acetyl-CoA carboxylase 1 (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FASN) and their nuclear transcription factor, sterol regulatory element binding protein-1c (SREBP-1c) (p < 0.05), was also increased. In vitro, intracellular lipid droplets and TG content in HepG2 cells increased under stimulation with GC or OA (p < 0.05); the increase was more significant following treatment with GC and OA together (p < 0.05). The ACC, SCD1, FASN and SREBP-1c mRNA expression changes were highly similar to the changes in TG content in cells. All the changes induced by GC disappeared when the glucocorticoid receptor (GR) was blocked by Mi.ConclusionsPostnatal overfeeding induced GC overexposure through 11β-HSD1 up-regulation in the liver. GC activated hepatic de novo lipogenesis (DNL) via GR and led to hepatic lipid accumulation, which increased the risk of NAFLD during adulthood.

Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways.

Non-alcoholic fatty liver disease(NAFLD) is a major public health concern worldwide. The aim of the present study was to observe the effect of diosgenin on NAFLD and investigate the underlying mechanisms. Diosgenin treatment increased the phosphorylation of AMP-activated protein kinase(AMPK) and acetyl-CoA carboxylase(ACC) in HepG2 cells. Diosgenin significantly inhibited high glucose(HG)-induced triglyceride (TG) accumulation and sterol regulatory element‑binding protein-1c(SREBP-1c) mRNA increase in HepG2 cells, which were partially abolished by the AMPK inhibitor compoundC. Diosgenin also significantly inhibited the increase of liver Xreceptor(LXR)α mRNA induced by HG or T0901317. However, T0901317‑induced upregulation of LXRα and SREBP-1c mRNA was not blocked by compoundC. Following a high-fat diet for 16weeks, the body and liver weights of the experimental rats were significantly increased, but this effect was significantly suppressed by diosgenin. Diosgenin and fenofibrate ameliorated lipid deposition in the liver and reduced the increase of hepatic TG content. Diosgenin significantly decreased the alanine aminotransferase(ALT) level, whereas fenofibrate significantly increased the ALT and aspartate aminotransferase levels. Diosgenin also increased AMPK and ACC phosphorylation and suppressed LXRα in the liver. Inconclusion, the results of the present study suggested that diosgenin is a potential agent for preventing the development of NAFLD through the AMPK and LXR signaling pathways.

Inhibition of 5-lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model.

Objective(s):Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model.Materials and Methods:Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea) was administrated.Results:Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS.Conclusion:AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function.

Similar to neoplastic tissues, growth and development of adipose tissue are thought to be angiogenesis-dependent. Since visceral adipose tissue (VAT) is associated with development and progression of nonalcoholic fatty liver disease (NAFLD), we hypothesized that angiogenesis inhibition would attenuate obesity-induced NAFLD. We fed C57BL/6J mice a low-fat diet (LFD, chow 10% kcal fat), a high-fat diet (HFD, 45% kcal fat) or HFD supplemented with the lemon-balm extract ALS-L1023 (HFD-ALS) for 15 weeks. ALS-L1023 reduced endothelial cell-tube formation in vitro. HFD increased VAT angiogenesis and induced weight gains including body weight, VAT mass and visceral adipocyte size compared with LFD. However, HFD-ALS led to weight reductions without affecting calorie intake compared with HFD. HFD-ALS also reduced serum ALT and AST levels and improved lipid metabolism. HFD-ALS suppressed steatosis, infiltration of inflammatory cells, and accumulation of collagen in livers. HFD-ALS modulated hepatic expression of genes involved in lipid metabolism, inflammation, fibrosis, antioxidation, and apoptosis. Concomitantly, analysis of VAT function revealed that HFD-ALS led to fewer CD68-positive macrophage numbers and lower expression of inflammatory cytokines compared with HFD. Our findings show that the anti-angiogenic herbal extract ALS-L1023 attenuates NAFLD by targeting VAT during obesity, suggesting that angiogenesis inhibitors could aid in the treatment and prevention of obesity-induced human NAFLD.

Promising effect of Rosa damascena extract on high-fat diet-induced nonalcoholic fatty liver

NAFLD is a chronic liver disease that affects a high proportion of the world's population which causes metabolic and hepatic damages. Rosa damascena Mill is traditionally used as a dietary supplement for liver disorders. This study was carried out to determine the beneficial effect of standardized extract of R. damascena on animal model of nonalcoholic fatty liver disease (NAFLD). NAFLD was induced by high-fat diet (HFD) in Wistar rats. HFD rats showed an increase (p < 0.05) in the plasma lipid levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and reduced the high-density lipoprotein (HDL) levels. R. damascena significantly reduced the elevation of final body weight, liver fat accumulation, TG, TC, LDL-C concentrations and hepatic enzymes (p < 0.05). Histopathological examination of hepatic tissue confirmed the therapeutic effect of R. damascena. Improvement of total antioxidant power activity, total thiol content, MPO enzyme activity, and also lipid peroxidation were also considered in treated animals (p < 0.05). HPLC analysis showed that phenolic compounds including gallic acid, quercetin and syringic acid are the main bioactive compounds of R. damascena hydroalcoholic extract. In conclusion, R. damascena dietary supplementation has a therapeutic effect in NAFLD. Improvement of oxidative stress associated damage in liver tissue is among the main pharmacological mechanisms involved in therapeutic activity of the plant.

Fat-1 mice prevent high-fat plus high-sugar diet-induced non-alcoholic fatty liver disease.

High-fat and high-sugar (HFS) diets have been suggested to play a causal role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate whether fat-1 transgenic mice with a higher tissue content of n-3 polyunsaturated fatty acids (PUFAs) could prevent HFS diet-induced NAFLD, compared with wild-type mice. The fat-1 and wild-type littermates had free access to a 15% fructose solution plus high-fat diet, a 15% glucose solution plus high-fat diet, or a 15% sucrose solution plus high-fat diet, respectively. Caloric intake, weight gain, biochemical parameters, histology, and gene and protein expression levels were measured after 8 weeks of intervention. Liquid intake in glucose- or sucrose-fed mice was about 2-fold compared with that in fructose-fed mice. The wild-type mice given glucose showed the highest total caloric intake and weight gain compared to the other groups. The serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and alanine transaminase (ALT) were significantly lowered in fat-1 groups compared with their paired wild-type groups. Histological analysis showed that the wild-type groups fed the HFS diets developed hepatic lipid accumulation and steatosis, compared with the fat-1 groups. The gene and protein expression levels involved in fatty acid synthesis and the toll-like receptor (TLR)-4 signaling pathway were significantly inhibited in the fat-1 groups compared with the wild-type groups. The endogenously synthesized n-3 PUFAs of the three fat-1 groups, which inhibit fatty acid synthesis and the TLR-4 signaling pathway, prevent HFS diet-induced NAFLD.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-κB signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response.

Effect of JAZF1 over-expression on high-fat diet-induced non-alcoholic fatty liver disease

Objective: To investigate the effects of juxtaposed with another zinc finger gene 1 (JAZF1) over-expression on the levels of pro-inflammatory cytokines in high-fat diet (HFD)-induced mouse fatty liver and its associated mechanisms. Methods: Twenty male C57BL/6J (3 weeks old) and 10 male JAZF1 transgenic (JAZF1-Tg) mice were randomly divided into three groups: wide-type with normal diet (NF group,n= 10), wide-type with high-fat diet (HF group,n= 10), and JAZF1-Tg with high-fat diet (HJ group,n= 10). All mice were fed with the corresponding diet for 12 weeks, and their food consumption and body weight were measured periodically. After 12 weeks, fasting blood glucose (FBG), insulin (INS), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), and alanine aminotransferase (ALT) in the blood and liver tissue from each group were measured. TG concentration in liver tissue was determined using an enzymatic assay, and the mRNA expression of tumor necrosis factor-α(TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) in the liver was measured by RT-PCR. In addition, the expression of p-JNK/JNK, p-p-38 MAPK/p-38 MAPK, p-ERK/ERK, IκBα, andβ-actin (reference) in the liver was determined using Western blot.. Results: (1) Body weight, FBG, INS, TC, and ALT were significantly reduced in the HJ group compared with those of the HF group (31.19±0.81 vs 36.07±1.43, 6.94±0.32 vs 8.14±0.36, 31.09±2.12 vs 45.21±3.34, 3.05±0.07 vs 3.81±0.08, 54.75±4.92 vs 68.09±5.15, respectively;P< 0.05). There were no significant differences in TG and FFA between the HJ and HF groups (0.72±0.05 vs 0.81±0.03, 0.81±0.4 vs 0.87±0.03; bothP> 0.05). (2) There was no significant difference in liver TG concentration between the HJ and HF groups (35.49±3.17 vs 38.26±3.59,P> 0.05). (3) Compared with the HF group, the HJ group had significantly reduced mRNA expression of TNF-α, MCP-1, and IL-8 (2.54TNF-αvs 8.64±0.73, 1.19±0.73,vs 3.93±0.18, 5.09±0.48 vs 9.09±0.89; allP< 0.01), significantly reduced protein expression of p-JNK and p-p-38 MAPK (0.92±0.06 vs 1.51±0.01, 1.07±0.04 vs 1.45±0.04; bothP< 0.01), and significantly increased protein expression of IκBα(0.99±0.06 vs 0.79±0.05,P< 0.01) in liver tissue. However, no significant difference was observed in the p-ERK level between the HJ and HF groups (P> 0.05). Conclusion: Upregulation of JAZF1 expression can significantly inhibit the expression of TNF-α, MCP-1, and IL-8 in the liver of mice on HFD. This attenuation may be closely associated with the reduced activation of the JNK, p-38 MAPK, and NF-κB pathways.

Increased susceptibility of prenatal food restricted offspring to high-fat diet-induced nonalcoholic fatty liver disease is intrauterine programmed

The present study aims to explore the mechanisms of fetal origin of high susceptibility to adult high-fat diet induced-nonalcoholic fatty liver disease in rat offspring undergoing intrauterine growth retardation (IUGR) induced by prenatal food restriction (FR) from gestational day 11 until full-term delivery. We observed that adult IUGR offspring rats exhibited gender-dependent catch-up growth with lower serum corticosterone (CORT) but up-regulation of the insulin-like growth factor 1 (IGF1) pathway, higher hepatic Kleiner scores and lower lipid export and oxidation. Furthermore, fetal IUGR offspring rats showed lower body weights with higher serum CORT but down-regulated IGF1 pathway, which was accompanied by enhanced lipid de novo synthetic gene expression, lower lipid output and oxidation gene expression. It is suggested that a “two-programming” mechanism, which refers to the adverse intrauterine programming of hepatic lipid de novo synthesis and glucocorticoid-IGF1 axis programming associated with postnatal catch-up growth, could explain the increased susceptibility.

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs—eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)—in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

Hepatoprotective Effects of Soybean Embryo by Enhancing Adiponectin-Mediated AMP-Activated Protein Kinase α Pathway in High-Fat and High-Cholesterol Diet-Induced Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), which is characterized by >5% deposition of triglycerides in hepatocytes, is often referred as a major risk factor for obesity, type 2 diabetes, and hypertension. We investigated the hepatoprotective effect of whole soybean embryos containing bioactive substances such as isoflavones and soyasaponins. For this study, mice were randomly allocated into four groups that were fed different diets for 10 weeks: normal diets and high-fat and high-cholesterol diets (HD), and HD with 10% or 20% soybean embryo powder (10SE-HD and 20SE-HD). Hepatic superoxide dismutase and glutathione peroxidase activity of the experimental groups increased during the period of the study (P < .05). Hepatic mRNA expressions of tumor necrosis factor α, nuclear factor (erythroid-derived 2)-like 2, and Caspase 3 were decreased when soybean embryos were increased in the mice's diets. Both of the soybean embryo-treated groups showed significantly decreased serum and liver triglyceride and total cholesterol. Adiponectin, AMP-activated protein kinase (AMPK) α, hydroxymethylglutaryl-CoA reductase, sterol regulatory element-binding protein-1c, fatty acid synthase, and apolipoprotein B mRNA expressions were decreased in the mice that were fed soybean embryos. We suggest that the regular supplementation of soybean embryos might be a useful treatment for preventing NAFLD and associated complications through upregulation of adiponectin-mediated AMPKα pathway parameters, which are implicated in antioxidant, anti-inflammatory, and lipid metabolism activities.

Effect of Alkaloids from Nelumbinis Plumula against Insulin Resistance of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

This study aimed to investigate the effects of total alkaloids from Nelumbinis Plumula (NPA) on insulin resistance (IR) of high-fat diet- (HFD-) induced nonalcoholic fatty liver disease (NAFLD). Rats were fed with HFD for 8 weeks to induce NAFLD. Then, the effect of NPA on ameliorating IR in HFD-induced NAFLD was evaluated. Fasting serum insulin was determined using an enzyme-linked immunosorbent assay (ELISA) kit for insulin following the manufacturer's protocol. Some inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were determined using ELISA kits to assess the inflammatory burden in rats. The results showed that HFD could induce a significant increase in blood glucose and IR in rats. However, rats treated with NPA (400 or 600 mg/kg) showed improved IR and reduction in serum inflammatory cytokines TNF-α and IL-6. Further investigation indicated that NPA could inhibit IR by restoring the insulin receptor substrate-1 (IRS-1) and suppressing the expression of c-Jun N-terminal kinase (JNK) phosphorylation. The present results supported the view that the pathogenesis of NAFLD was complex with inflammation, together with increasing serum glucose and IR. Also, JNK and IRS phosphorylation were suggested for their involvement in the modulating of IR during NAFLD progression. Therefore, NPA may serve as a potential natural remedy against IR in NAFLD.

Perilla Oil Has Similar Protective Effects of Fish Oil on High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Gut Dysbiosis.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in developed countries. Recent studies indicated that the modification of gut microbiota plays an important role in the progression from simple steatosis to steatohepatitis. Epidemiological studies have demonstrated consumption of fish oil or perilla oil rich in n-3 polyunsaturated fatty acids (PUFAs) protects against NAFLD. However, the underlying mechanisms remain unclear. In the present study, we adopted 16s rRNA amplicon sequencing technique to investigate the impacts of fish oil and perilla oil on gut microbiomes modification in rats with high-fat diet- (HFD-) induced NAFLD. Both fish oil and perilla oil ameliorated HFD-induced hepatic steatosis and inflammation. In comparison with the low-fat control diet, HFD feeding significantly reduced the relative abundance of Gram-positive bacteria in the gut, which was slightly reversed by either fish oil or perilla oil. Additionally, fish oil and perilla oil consumption abrogated the elevated abundance of Prevotella and Escherichia in the gut from HFD fed animals. Interestingly, the relative abundance of antiobese Akkermansia was remarkably increased only in animals fed fish oil compared with HFD group. In conclusion, compared with fish oil, perilla oil has similar but slightly weaker potency against HFD-induced NAFLD and gut dysbiosis.

Gastric bypass surgery is protective from high-fat diet-induced non-alcoholic fatty liver disease and hepatic endoplasmic reticulum stress.

High-fat diets are known to contribute to the development of obesity and related co-morbidities including non-alcoholic fatty liver disease (NAFLD). The accumulation of hepatic lipid may increase endoplasmic reticulum (ER) stress and contribute to non-alcoholic steatohepatitis and metabolic disease. We hypothesized that bariatric surgery would counter the effects of a high-fat diet (HFD) on obesity-associated NAFLD. Sixteen of 24 male Sprague Dawley rats were randomized to Sham (N=8) or Roux-en-Y gastric bypass (RYGB) surgery (N=8) and compared to Lean controls (N=8). Obese rats were maintained on a HFD throughout the study. Insulin resistance (HOMA-IR), and hepatic steatosis, triglyceride accumulation, ER stress and apoptosis were assessed at 90days post-surgery. Despite eating a HFD for 90days post-surgery, the RYGB group lost weight (-20.7±6%, P<0.01) and improved insulin sensitivity (P<0.05) compared to Sham. These results occurred with no change in food intake between groups. Hepatic steatosis and ER stress, specifically glucose-regulated protein-78 (Grp78, P<0.001), X-box binding protein-1 (XBP-1) and spliced XBP-1 (P<0.01), and fibroblast growth factor 21 (FGF21) gene expression, were normalized in the RYGB group compared to both Sham and Lean controls. Significant TUNEL staining in liver sections from the Obese Sham group, indicative of accelerated cell death, was absent in the RYGB and Lean control groups. Additionally, fasting plasma glucagon like peptide-1 was increased in RYGB compared to Sham (P<0.02). These data suggest that in obese rats, RYGB surgery protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis.

Lycium ruthenicum extract alleviates high-fat diet-induced nonalcoholic fatty liver disease via enhancing the AMPK signaling pathway.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that currently has no standard treatment. The present study aimed to evaluate the effects of Lycium ruthenicum extract (LRE) on high‑fat diet (HFD)-induced NAFLD, and elucidate the underlying molecular mechanisms. To determine the hepatoprotective effect of LRE, C57BL/6 mice were fed a normal control diet, high‑fat diet (HFD), HFD supplemented with 2 g/kg LRE, or HFD supplemented with 5 g/kg LRE. Treatment with LRE markedly decreased the levels of triglycerides, total cholesterol, aspartate aminotransferase and alanine aminotransferase in the serum of mice fed a HFD, and improved glucose metabolism and insulin sensitivity in NAFLD mice. In addition, treatment with LRE significantly decreased the expression levels of sterol regulatory element‑binding protein 1c and fatty acid synthase, and markedly increased the expression of peroxisome proliferator‑activated receptor α and peroxisome proliferator‑activated receptor γ co‑activator 1α. Furthermore, LRE treatment significantly increased the activation of adenosine monophosphate‑activated protein kinase (AMPK) in the liver. These results suggested that LRE is able to suppress lipid accumulation in HFD‑fed C57BL/6 mice via enhancement of the AMPK pathway.

Discovery of a Potent 9-Deazaxanthine-based Agent for the Treatment of Obesity-Related Non-alcoholic Fatty Liver Disease.

A series of deazaxanthine-based derivatives were rationally prepared and evaluated. 8g exhibited the most potent glucose-lowering effect on HepG2 cell line and modulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 8g at 25 mg/kg/day for 4 weeks manifested therapeutic effects on high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) by decreasing the weights of the body, liver, and fat. 8g also modulated the serum levels of fasting glucose and adiponectin, triglycerides, low-density lipoprotein-cholesterol, and alanine aminotransferase, as well as the hepatic concentrations of triglycerides, total cholesterol. Moreover, 8g significantly decreased steatosis and blocked the increase of adipocytes and the size of adipose tissues from NAFLD. In the DIO mice model, 8g ameliorated the obesity-related symptoms and normalized serum biomarkers.

Beneficial effects of neomangiferin on high fat diet-induced nonalcoholic fatty liver disease in rats

This study was carried out to determine the effect and mechanism of action of neomangiferin (NG) on high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in rats. NAFLD rats were randomly assigned into several groups of equal number. NG (50, 25mg/kg·day(-1) BW) and lipanthyl (PT, 5mg/kg·day(-1) BW) were given to the NAFLD rats, respectively. In the study, serum lipids, metabolic rate, liver fat, liver lipids and histology were examined. To further investigate the molecular mechanism of the effect of NG on NAFLD, expression levels of mRNA and protein for peroxisome proliferator-activated receptor α (PPARα), fatty acid transport protein 2 (FATP2), long-chain-fatty-acid - CoA ligase 1 (ACSL1) and carnitine palmitoyltransferase 1a (CPT1a) in the liver were determined by Real Time-PCR and western blot analysis, respectively. NG administration significantly reduced the final body weight, liver fat accumulation, and serum triglyceride (TG), total cholesterol (TC) concentrations, low-density lipoprotein cholesterol (LDL-C), glucose (GLU) levels, and hepatic TG, TC, malondialdehyde (MDA) levels, but increased serum high-density lipoprotein cholesterol (HDL-C) and hepatic superoxide dismutase (SOD) levels. NG upregulated the mRNA and protein expression of PPARα and CPT1a, but downregulated the mRNA and protein expression of FATP2 and ACSL1 in the liver. These results suggested that NG can regulate NAFLD partly by modulating the expression levels of genes involved in FFA uptake and lipid oxidation.