Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr-/- mice

The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.     

PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver

Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.     

Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Whereas simple steatosis has a benign clinical course, steatohepatitis is a recognized cause of progressive liver fibrosis and can develop into cirrhosis. NAFLD and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in United States general population with a prevalence of 20% and 3%, respectively. Hepatic steatosis is frequently associated with obesity, type 2 diabetes, and hyperlipidemia with insulin resistance as a key pathogenic factor. A two-hit theory best describes the progression from simple steatosis to NASH, fibrosis, or cirrhosis. These two hits consist of the accumulation of excessive hepatic fat primarily owing to insulin resistance, and oxidative stress owing to reactive oxygen species (ROS). Mitochondria are the major cellular source of ROS in cases of NASH. Currently, treatment is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Antioxidants such as vitamin E, N-acetylcysteine, betaine, and others may be beneficial in the treatment of NASH.     

Lactoferrin Prevents Hepatic Injury and Fibrosis via the Inhibition of NF-κB Signaling in a Rat Non-Alcoholic Steatohepatitis Model

Non-alcoholic steatohepatitis (NASH) can cause liver cirrhosis and hepatocellular carcinoma (HCC), with cases increasing worldwide. To reduce the incidence of liver cirrhosis and HCC, NASH is targeted for the development of treatments, along with viral hepatitis and alcoholic hepatitis. Lactoferrin (LF) has antioxidant, anti-cancer, and anti-inflammatory activities. However, whether LF affects NASH and fibrosis remains unelucidated. We aimed to clarify the chemopreventive effect of LF on NASH progression. We used a NASH model with metabolic syndrome established using connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rats. Cx32ΔTg rats (7 weeks old) were fed a high-fat diet and intraperitoneally injected with dimethylnitrosamine (DMN). Rats were divided into three groups for LF treatment at 0, 100, or 500 mg/kg/day for 17 weeks. Lactoferrin significantly protected steatosis and lobular inflammation in Cx32ΔTg rat livers and attenuated bridging fibrosis or liver cirrhosis induced by DMN. By quantitative RT–PCR, LF significantly down-regulated inflammatory (Tnf-α, Il-6, Il-18, and Il-1β) and fibrosis-related (Tgf-β1, Timp2, and Col1a1) cytokine mRNAs. Phosphorylated nuclear factor (NF)-κB protein decreased in response to LF, while phosphorylated JNK protein was unaffected. These results indicate that LF might act as a chemopreventive agent to prevent hepatic injury, inflammation, and fibrosis in NASH via NF-κB inactivation.     

Alisol B Alleviates Hepatocyte Lipid Accumulation and Lipotoxicity via Regulating RARα-PPARγ-CD36 Cascade and Attenuates Non-Alcoholic Steatohepatitis in Mice

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated from Alisma orientalis (Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl₄)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.     

Consumption of Low Dose Fucoxanthin Does Not Prevent Hepatic and Adipose Inflammation and Fibrosis in Mouse Models of Diet-Induced Obesity

Fucoxanthin (FCX) is a xanthophyll carotenoid present in brown seaweed. The goal of this study was to examine whether FCX supplementation could attenuate obesity-associated metabolic abnormalities, fibrosis, and inflammation in two diet-induced obesity (DIO) mouse models. C57BL/6J mice were fed either a high-fat/high-sucrose/high-cholesterol (HFC) diet or a high-fat/high-sucrose (HFS) diet. The former induces more severe liver injury than the latter model. In the first study, male C57BL/6J mice were fed an HFC diet, or an HFC diet containing 0.015% or 0.03% (w/w) FCX powder for 12 weeks to develop obesity-induced nonalcoholic steatohepatitis (NASH). In the second study, mice were fed an HFS diet or an HFS diet containing 0.01% FCX powder for 8 weeks. FCX did not change body weight gain and serum lipid profiles compared to the HFC or HFS controls. No significant differences were present in liver triglyceride and total cholesterol, hepatic fat accumulation, and serum alanine aminotransferase levels between control and FCX-fed mice regardless of whether they were on an HFC or HFS diet. FCX did not mitigate mRNA abundance of genes involved in lipid synthesis, cholesterol metabolism, inflammation, and fibrosis in the liver and white adipose tissue, while hepatic fatty acid β-oxidation genes were significantly elevated by FCX in both HFC and HFS feeding studies. Additionally, in the soleus muscle, FCX supplementation significantly elevated genes that regulate mitochondrial biogenesis and fatty acid β-oxidation, concomitantly increasing mitochondrial DNA copy number, compared with HFC. In summary, FCX supplementation had minor effects on hepatic and white adipose inflammation and fibrosis in two different DIO mouse models.     

Switching to Regular Diet Partially Resolves Liver Fibrosis Induced by High-Fat,High-Cholesterol Diet in Mice

The globally prevalent disease, non-alcoholic steatohepatitis (NASH), is characterized by a steatotic and inflammatory liver. In NASH patients, tissue repair mechanisms, activated by the presence of chronic liver damage, lead to the progressive onset of hepatic fibrosis. This scar symptom is a key prognostic risk factor for liver-related morbidity and mortality. Conflicting reports discuss the efficiency of dietary interventions on the reversibility of advanced fibrosis established during NASH. In the present study, the effect of dietary interventions was investigated in the outcome of the fibrosis settled in livers of C57BL/6J mice on a high-fat, high-cholesterol diet (HFHCD) for 5 or 12 consecutive weeks. Various clinico-pathological investigations, including a histological analysis of the liver, measurement of plasma transaminases, steatosis and fibrosis, were performed. To assess the effectiveness of the dietary intervention on established symptoms, diseased mice were returned to a standard diet (SD) for 4 or 12 weeks. This food management resulted in a drastic reduction in steatosis, liver injuries, inflammatory markers, hepatomegaly and oxidative stress and a gradual improvement in the fibrotic state of the liver tissue. In conclusion, our results demonstrated that dietary intervention can partially reverse liver fibrosis induced by HFHCD feeding.     

N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis

A "2-hit" model for nonalcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the "first hit" and sensitizes the liver to potential "second hits" resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, has been suggested as a dietary therapy for NASH. We examined the effects of NAC in a rat total enteral nutrition (TEN) model where NASH develops as the result of overfeeding dietary polyunsaturated fat. Male Sprague-Dawley rats consumed pelleted AIN-93G diets ad libitum or were overfed a 9200 kJ.kg(-0.75).d(-1) liquid diet containing 70% corn oil with or without 2 g.kg(-1).d(-1) NAC i.g. for 65 d. Hepatic steatosis was not influenced by dietary supplementation with NAC; however, the liver pathology score was lower (P 相似文献   

Neonatal exposure to genistein ameliorates high-fat diet-induced non-alcoholic steatohepatitis in rats

Non-alcoholic steatohepatitis (NASH) is becoming a prevalent disease in developing countries with no effective therapy. Isoflavones such as genistein have been shown to prevent NASH in a rat model, but the effects of neonatal exposure to genistein on lipid metabolism have been rarely studied. In the present study, three doses of genistein (30, 300 or 1200?μg/rat per d) were injected (subcutaneously) into neonatal male Sprague-Dawley rats at postnatal days 1-5. After weaning, these rats were allowed free access to a high-fat diet for 6 weeks. The results demonstrate that NASH was induced by high fat feeding in the control rats, whereas genistein-treated rats displayed smaller body weight, and lower hepatic inflammation and steatosis. The mid dose of genistein was most effective. Neonatal exposure to genistein also resulted in a lower incidence of apoptotic cells in the liver. Additionally, neonatal genistein-treated rats showed lower hepatic expression of fatty acid synthase and sterol regulatory element-binding protein-1, but higher expression of PPARα, indicative of lower rates of lipid synthesis and higher rates of β-oxidation. These results indicate that neonatal treatment with genistein has a prolonged effect on hepatic lipid metabolism that is maintained post-weaning, offering a potential approach for the prevention of hepatic steatosis and NASH.     

Alanyl-Glutamine Protects Mice against Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis and Fibrosis by Modulating Oxidative Stress and Inflammation

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease with increasing prevalence rates over years and is associated with hepatic lipid accumulation, liver injury, oxidative stress, hepatic inflammation, and liver fibrosis and lack of approved pharmacological therapy. Alanyl-glutamine (Ala-Gln) is a recognized gut-trophic nutrient that has multiple pharmacological effects in the prevention of inflammation- and oxidative-stress-associated diseases. Nevertheless, whether Ala-Gln has a protective effect on NASH still lacks evidence. The aim of this study is to explore the influence of Ala-Gln on NASH and its underlying mechanisms. Here, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet to establish the model of NASH, and Ala-Gln at doses of 500 and 1500 mg/kg were intraperitoneally administered to mice along with a MCD diet. The results showed that Ala-Gln treatment significantly attenuated MCD-induced hepatic pathological changes, lowered NAFLD activity score, and reduced plasma alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels. Ala-Gln dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). In addition, Ala-Gln exerted an anti-oxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, Ala-Gln exhibited an anti-inflammatory effect via decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators. Notably, Ala-Gln suppressed the development of liver fibrosis in MCD-diet-fed mice, which may be due to the inhibition of hepatic stellate cells activation. In conclusion, these findings revealed that Ala-Gln prevents the progression of NASH through the modulation of oxidative stress and inflammation and provided the proof that Ala-Gln might be an effective pharmacological agent to treat NASH.     

La stéatopathie dysmétabolique ou NASH : faut-il dépister les patients à haut risque atteints de diabète de type 2 ou d’obésité ?

Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. It encompasses a spectrum of phenotypes including benign hepatic steatosis (NAFL) and nonalcoholic steatohepatitis (NASH) which is considered as the progressive form with higher risk of progression towards liver fibrosis, cirrhosis or hepatocellular carcinoma. NAFLD remains asymptomatic until end-stage of the disease and is largely underdiagnosed. In the last decades, populations at high risk of progression to advanced fibrosis, such as obese and type 2 diabetic (T2D) patients, have been identified. The presence of advanced fibrosis has been identified as the major determinant of overall and hepatic mortality. Liver biopsy remains the gold standard for the diagnosis of NASH and hepatic fibrosis, however several noninvasive blood-based and imaging-based biomarkers have been developed for the assessment and screening for liver fibrosis. Finally, the lifestyle modification and weight loss intervention improve steatosis, NASH and liver fibrosis, and therapeutic clinical trials for the treatment of NASH are an area of intensive research. This review article will summarize the current evidence supporting the systematic screening for advanced fibrosis in high-risk population such as T2D and obese patients. Several modalities are available for such screening. However, additional studies are needed to determine the optimal strategy for a systematic screening in high risk population and to allow efficient and cost-effectiveness pathway referral in hepatology clinics.     

Serological biomarkers associate ultrasound characteristics of steatohepatitis in mice with liver cancer

Background

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of lesions ranging from steatosis to a complex pattern, nonalcoholic steatohepatitis (NASH). Ultrasonography provides important information on hepatic architecture for steatosis. NASH patients have an increased risk of hepatocellular carcinoma (HCC). Early detection of NASH is critical for clinicians to advise on necessary treatments to prevent the onset of HCC.

Methods

We established a NASH-HCC mouse model using diethylnitrosamine as a carcinogen to induce HCC and a high-fat diet to induce metabolic disorders. Characteristics of ultrasound imaging and potential serum biomarkers were investigated for detection of steatohepatitis and HCC in mice.

Results

The data suggested that ultrasound imaging of hyperechoic masses was potentially linked to the gross finding of HCC nodules, which was further confirmed by the histology. Positive correlation between serum fibroblast growth factor 15 and acoustic attenuation coefficient was found in mice with steatohepatitis. Combined with the serum markers, the increased acoustic attenuation coefficient could be a useful diagnostic parameter of ultrasound imaging for NASH detection.

Conclusions

This study demonstrates that a combination of serum fibroblast growth factor 15 and acoustic attenuation coefficient could be a sensitive marker for steatohepatitis and to predict carcinogenic initiation and progression of HCC in mice. These results might help for the design of ultrasound and surrogate markers in screening NASH patients who could be at risk of HCC.

     

Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease,Hepatic Fibrosis,and Insulin Resistance in Mice

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD⁺) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.     

Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax

Hepatocyte apoptosis in addition to oxidative stress could be a key component in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms of hepatocellular apoptotic response associated with oxidative stress have not been investigated in high-fat diet (HFD)-induced NASH models. In this study, Sprague-Dawley rats were fed either a Lieber-DeCarli control diet (CD; 35% energy from fat) or a HFD (71% energy from fat) for 6 wk. Pathologic lesions, lipid peroxidation products, and apoptotic hepatocytes in the liver were examined. The expressions of hepatic tumor necrosis factor-alpha (TNFalpha) and protein concentrations of cleaved caspase-3, cytochrome p4502E1 (CYP2E1), phosphorylated c-Jun NH(2)-terminal kinase (JNK), Bax, Bcl-2, and Bcl-xl were measured. Results showed that the key histological features of NASH, including steatosis, inflammatory cell infiltration, and ballooning degeneration of hepatocytes, were induced by HFD feeding, with increased hepatic TNFalpha mRNA expression. HFD-fed rats had elevated lipid peroxidation products and CYP2E1 protein in the liver. The apoptotic hepatocytes were significantly greater in livers of rats fed HFD than in those fed CD, and these were associated with a higher level of cleaved caspase-3. In addition, HFD feeding increased both hepatic phosphorylated JNK and pro-apoptotic Bax but did not affect anti-apoptotic Bcl-2 and Bcl-xl compared with CD feeding. These data indicate that the increased oxidative stress and its associated JNK activation as well as an imbalance of pro- and anti-apoptotic proteins in the Bcl-2 family all contribute to high hepatocyte apoptosis that may play an important role in the pathogenesis of NASH in this model.     

Supplementation with Vitis vinifera L. skin extract improves insulin resistance and prevents hepatic lipid accumulation and steatosis in high-fat diet–fed mice

Nonalcoholic fatty liver disease is one of the most common complications of obesity. The Vitis vinifera L. grape skin extract (ACH09) is an important source of polyphenols, which are related to its antioxidant and antihyperglycemic activities. We hypothesized that ACH09 could also exert beneficial effects on metabolic disorders associated with obesity and evaluated ACH09’s influence on high-fat (HF) diet–induced hepatic steatosis and insulin resistance in C57BL/6 mice. The animals were fed a standard diet (10% fat, control) or an HF diet (60% fat, HF) with or without ACH09 (200 mg/[kg d]) for 12 weeks. Our results showed that ACH09 reduced HF diet–induced body weight gain, prevented hepatic lipid accumulation and steatosis, and improved hyperglycemia and insulin resistance. The underlying mechanisms of these beneficial effects of ACH09 may involve the activation of hepatic insulin-signaling pathway because the expression of phosphorylated insulin receptor substrate-1, phosphatidylinositol 3-kinase, phosphorylated Akt serine/threonine kinase 1, and glucose transporter 2 was increased by ACH09 and correlated with improvement of hyperglycemia, hyperinsulinemia, and insulin resistance. ACH09 reduced the expression of the lipogenic factor sterol regulatory-element binding protein-1c in the liver and upregulated the lipolytic pathway (phosphorylated liver kinase B1/phosphorylated adenosine-monophosphate–activated protein kinase), which was associated with normal hepatic levels of triglyceride and cholesterol and prevention of steatosis. ACH09 prevented the hepatic oxidative damage in HF diet–fed mice probably by restoration of antioxidant activity. In conclusion, ACH09 protected mice from HF diet–induced obesity, insulin resistance, and hepatic steatosis. The regulation of hepatic insulin signaling pathway, lipogenesis, and oxidative stress may contribute to ACH09’s protective effect.     

Chronic consumption of fructose in combination with <Emphasis Type="Italic">trans</Emphasis> fatty acids but not with saturated fatty acids induces nonalcoholic steatohepatitis with fibrosis in rats

Purpose

Consumption of Western diet high in fat and fructose has been attributed to the recent epidemic of nonalcoholic fatty liver disease (NAFLD). However, the impact of specific fatty acids on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is poorly understood. In the present study, we investigated the chronic effects of consumption of fructose in combination with saturated fatty acids (SFA) or trans fatty acids (TFA) on the development of NAFLD.

Methods

Male Sprague–Dawley rats were randomly assigned to six isocaloric starch/high fructose (44% of calories), high fat (39% calories) diet containing either starch–peanut oil, fructose–peanut oil, fructose–palmolein, fructose–clarified butter, fructose–coconut oil or fructose–partially hydrogenated vegetable oil and fed for 24 weeks. Palmolein, clarified butter and coconut oil were used as the source of SFA whereas partially hydrogenated vegetable oil was used as the source of TFA. Peanut oil was used as the reference oil.

Results

Long-term feeding of fructose in combination with SFA or TFA induced hepatic steatosis of similar extent associated with upregulation of stearoyl CoA desaturase-1. In contrast, fructose in combination with TFA induced NASH with fibrosis as evidenced by upregulation of hepatic proinflammatory cytokine and fibrogenic gene expression, increased hepatic oxidative stress and adipocytokine imbalance. Histopathological analysis revealed the presence of NASH with fibrosis. Further, peanut oil prevented the development of NAFLD in fructose-fed rats.

Conclusion

Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.

     

Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

In this study, the protective effect of the total saponins from Rosa laevigata Michx (RLTS) against liver fibrosis induced by carbon tetrachloride (CCl₄) in rats was evaluated. The results showed that RLTS significantly rehabilitated the levels of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione, glutathione peroxidase, catalase, superoxide dismutase, hydroxyproline, α-smooth muscle actin, collagen I, collagen III and fibronectin, which were confirmed using H&E, Sirius Red and Masson histopathological assays. Further research indicated that RLTS markedly reduced cytochrome P450 2E1 activity, attenuated oxidative stress, and suppressed inflammation. In addition, RLTS facilitated matrix degradation through down-regulation of matrix metalloproteinase2, matrix metalloproteinase 9 and metalloproteinases1, and exerted the anti-fibrotic effects through affecting transforming growth factor β/Smad, focal adhesion kinase/phosphatidylinositol-3-kinase/amino kinase terminal/70-kDa ribosomal S6 Kinase (FAK-PI3K-Akt-p70^S6K) and mitogen-activated protein kinase (MAPK) signaling pathways. Taken together, our data indicate that RLTS can be applied as one effective candidate for the treatment of liver fibrosis in the future.