Temporal Development of Dyslipidemia and Nonalcoholic Fatty Liver Disease (NAFLD) in Syrian Hamsters Fed a High-Fat,High-Fructose,High-Cholesterol Diet

The use of translationally relevant animal models is essential, also within the field of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Compared to frequently used mouse and rat models, the hamster may provide a higher degree of physiological similarity to humans in terms of lipid profile and lipoprotein metabolism. However, the effects in hamsters after long-term exposure to a NASH diet are not known. Male Syrian hamsters were fed either a high-fat, high-fructose, high-cholesterol diet (NASH diet) or control diets for up to 12 months. Plasma parameters were assessed at two weeks, one, four, eight and 12 months and liver histopathology and biochemistry was characterized after four, eight and 12 months on the experimental diets. After two weeks, hamsters on NASH diet had developed marked dyslipidemia, which persisted for the remainder of the study. Hepatic steatosis was present in NASH-fed hamsters after four months, and hepatic stellate cell activation and fibrosis was observed within four to eight months, respectively, in agreement with progression towards NASH. In summary, we demonstrate that hamsters rapidly develop dyslipidemia when fed a high-fat, high-fructose, high-cholesterol diet. Moreover, within four to eight months, the NASH-diet induced hepatic changes with resemblance to human NAFLD.     

Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

NAFLD is the world’s most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.     

The Ethanol Extract from Lonicera japonica Thunb. Regresses Nonalcoholic Steatohepatitis in a Methionine- and Choline-Deficient Diet-Fed Animal Model

Nonalcoholic steatohepatitis (NASH) is characterized as fat accumulation in the hepatic tissue associated with various degrees of inflammation and progressive fibrosis. The potent anti-inflammatory and ethnopharmacological properties of Lonicera japonica Thunb. (Caprifoliaceae) make it an excellent source of novel medicinal targets for the treatment of NASH. The aim of the study was to investigate the effects of L. japonica ethanol extract (LJEE) on NASH in mice. C57BL/6J mice were fed with methionine-choline-deficient diet (MCDD) for eight weeks to promote the development of NASH. After development of the model, the mice were administered LJEE once daily via oral gavage at doses of 100, 200, or 300 mg/kg for another four weeks. Simultaneous treatments with LJEE (300 mg/kg/day) resulted in pronounced improvements in liver steatosis, ballooning degeneration, and inflammation. LJEE prevented MCDD-induced plasma level increases in aspartate aminotransferase and alanine aminotransferase. LJEE significantly reduced hepatic malondialdehyde level and ameliorated hepatic inflammation and fibrosis in MCDD-fed mice, which were associated with down-regulation of cytochrome P450 2E1 suppression of multiple proinflammatory and profibrotic genes. LJEE can prevent hepatic steatosis by reducing hepatic peroxisome acyl-CoA:diacylglycerol acyltransferase 2 expression, as well as by inducing proliferator-activated receptor α expression. In addition, the LJEE treatments caused significant reduction in the phosphorylated form of Jun N-terminal kinase along with an increase in the phosphorylated level of extra cellular signal-regulated kinase 1/2. Our study demonstrated the protective role of LJEE in ameliorating nutritional steatohepatitis.     

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.     

Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study

OBJECTIVE: In experimental animals, recent results suggest that the addition of inulin-type fructans such as oligofructose (OFS) in the diet decreases triacylglycerol accumulation in the liver tissue. Therefore, we have investigated the effect of daily ingestion of OFS in seven patients with nonalcoholic steatohepatitis (NASH), confirmed by liver biopsies. DESIGN: They received 16 g/day OFS or maltodextrine (placebo) for 8 weeks in a randomized double-blind crossover design. Energy intake, body composition, liver steatosis and blood parameters were analysed after 4 and 8 weeks of dietary supplementation. RESULTS: Compared to placebo, OFS decreased significantly serum aminotransferases, aspartate aminotransferase after 8 weeks, and insulin level after 4 weeks, but this could not be related to significant effect on plasma lipids. CONCLUSION: This pilot study supports the putative interest of OFS in the management of liver diseases associated with abnormal lipid accumulation in humans.     

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.     

Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Resveratrol is a polyphenolic compound with antioxidant capacity that shows beneficial effects on down-regulation of inflammatory mediators and metabolic disorders. We hypothesized that supplementation with resveratrol can further improve the efficacy of lifestyle modifications in the management of NAFLD. In this randomized, double-blinded, controlled clinical trial, 50 NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and received physical activity recommendations. Serum liver enzymes, inflammatory markers, hepatic steatosis and fibrosis, dietary intake, anthropometric measurements, and physical activity were assessed at both baseline and the end of the study. In both groups, anthropometric measurements (weight, body mass index, waist circumference), liver enzymes, and steatosis grade improved (P < 005). Resveratrol supplementation was associated with a significant reduction in liver enzyme alanine aminotransferase, inflammatory cytokines, nuclear factor κB activity, serum cytokeratin-18, and hepatic steatosis grade, as compared with placebo supplementation (P < .05). For the treatment of NAFLD, our results showed that 12 weeks of supplementation of 500 mg resveratrol, along with lifestyle modification, is superior to lifestyle modification alone. This is at least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis. More studies are needed to confirm and increase the clinical application of the present results.     

Place de l’Activité Physique Adaptée dans le parcours de soins : cas du patient présentant une stéatose hépatique non-alcoolique (NAFLD)

Non-Alcoholic Fatty Liver Disease (NAFLD) is estimated to affect 26% of men and 11% of women in France. NAFLD is a continuum of liver damage ranging from, simple steatosis, to non-alcoholic steatohepatitis (NASH), NASH with liver fibrosis and sometimes post-NASH cirrhosis. NAFLD is favored by excess weight (overweight or obesity) associated with systemic metabolic abnormalities affecting particularly, adipose tissue and striated muscles. The preventive and curative treatment of NAFLD is based on hygienic and dietary measures. These measures have proven to be effective in terms of resolution of NASH and stabilization or even regression of liver fibrosis. The implementation of a program of adapted physical activity (APA), by a competent professional, contributes significantly to the improvement of the clinical state independently of weight loss. At the molecular level, the current literature emphazises the pleiotropic effect of this management, particularly through its direct or indirect action on local (e.g. hepatic) and systemic metabolism, the systemic inflammatory state and rheological activity. Beyond these pathophysiological repercussions, the APA professional accompanies the patient with a chronic disease, in this case NAFLD, to induce a sustainable lifestyle change by focusing on his or her motivational state. These measures appear to be beneficial for both adults and children.     

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.     

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   

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.     

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.     

Relation of Dietary Patterns and Nutritional Profile to Hepatic Fibrosis in a Sample of Lebanese Non-Alcoholic Fatty Liver Disease Patients

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver injury worldwide. NAFLD can evolve into non-alcoholic steatohepatitis (NASH) with or without fibrosis. The objectives of this study were to determine the nutritional profile and dietary patterns of NAFLD Lebanese patients and to report the type of diet-related to the presence of hepatic fibrosis. We hypothesized that the traditional pattern was related to a low risk of fibrosis. This cross-sectional study included 320 eligible Lebanese NAFLD patients. Three dietary patterns were identified: the Traditional diet, the High Fruit diet, and the Westernized diet. Multivariate analysis showed a significant relationship between high adherence to the traditional diet and absence of hepatic fibrosis with a decreased risk of 82%, p = 0.031 after adjusting for its covariables. Fruits were absent from this dietary pattern. Although our results pointed to a possible relationship between fibrosis in NAFLD patients and fruit intake, experimental studies are needed to show whether this is a causal relationship. However, the results obtained in this study may contribute to the planning of dietary interventions and recommendations and enable a better follow-up for NAFLD patients with fibrosis.     

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.     

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.     

Anti-Obesity Effects of Aqueous Extracts of Sunbanghwalmyung-Eum in High-Fat- and High-Cholesterol-Diet-Induced Obese C57BL/6J Mice

Sunbanghwalmyung-eum (SBH) is a traditional herbal medicine that exhibits various pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. In this study, we investigated the systemic anti-obesity effects of an aqueous extract of SBH in the liver, adipose, and muscle tissue from high-fat and high-cholesterol diet (HFHCD)-induced obese C57BL/6J mice. After 6 weeks of an HFHCD, the mice were continuously fed HFHC with oral administration of SBH (100 mg/kg/day), Sim (simvastatin, 5 mg/kg/day, positive control), or water (HFHC only) for another 6 weeks. Our results showed that SBH attenuated the HFHCD-induced body weight gain and fat accumulation in the liver, and improved plasma lipid levels, such as those of triglycerides (TGs), blood total cholesterol (TC), and low-density lipoprotein (LDL-c). SBH and Sim inhibited the inflammation accompanied by obesity via decreasing inflammatory cytokine interleukin (IL)-1β, tumor necrosis factor α (TNFα), and monocyte chemoattractant protein 1 (MCP1). Moreover, SBH downregulated the expression of protein levels of adipogenic-related factors, including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in the liver, adipose, and muscle tissue. The SBH and Sim treatment also significantly upregulated the phosphorylation of AMP-activated protein kinase α (AMPKα) in the liver and hormone-sensitive lipase (HSL) in the adipose tissue. Overall, the effects of SBH on HFHCD-induced obesity were similar to or more potent than those of simvastatin. These results indicated that SBH has great potential as a therapeutic herbal medicine for obesity.     

The Efficacy of an Energy-Restricted Anti-Inflammatory Diet for the Management of Obesity in Younger Adults

There is growing evidence of the dietary impact on obesity-induced low-grade chronic inflammation and the associated chronic non-communicable diseases modification. We determined changes in body composition and cardiometabolic and inflammatory status of participants with obesity after 24 weeks of a dietary intervention based on an energy-reduced anti-inflammatory diet and examined the relationship of these changes with changes in the inflammatory potential of the diet. The anthropometric and body composition parameters of 81 participants (average age of 43 years, 74 women) were assessed. Metabolic status was determined using the glycemic and lipid statuses, and the cardiometabolic index and inflammatory status were determined using the concentration of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α). The inflammatory potential of the diet was assessed using the Dietary Inflammatory Index (DII^®). Intervention with an anti-inflammatory diet resulted in a significant reduction in body weight and visceral adipose tissue and caused improvements in the participants’ cardiometabolic and inflammatory statuses. The anti-inflammatory diet was shown to be effective regarding obesity management. The study data could advance current scientific knowledge in the field of inflammation and diet, provide guidelines for obesity management, and find its application in routine clinical practice.     

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.