Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

A Cross Sectional Study on the Correlation between Waist Circumference and Fatty Liver on Ultrasonography among Non-Alcoholic Filipino Adults

Objectives: This study aimed to determine the correlation between waist circumference and fatty liver on ultrasonography among non-alcoholic Filipino adults. This will aid in detecting non-alcoholic fatty liver disease in its early course, hence improving our current therapeutic recommendations in preventing and managing the adverse health outcomes of NAFLD. Methods and Materials: A cross-sectional study with a total of 65 recruited participants. The data collected were age, sex, waist-circumference, co-morbidities with maintenance medications, history of alcohol intake with emphasis on the quantity and duration, and history of drug intake. Waist circumference was measured and recorded. The presence of NAFLD was determined through a review of the ultrasonography results of all subjects. The demographic profile and waist circumference of all subjects were described using descriptive statistics. The chi-square test was utilized to test the independence of the NAFLD and WC in the quartile. Pearson correlation was used to determine the linear relationship between the variables. Pearson correlation coefficient was statistically significant at p 0.05. Results: Among the subjects, 26 (42%) presented with fatty liver based on ultrasonography, 15 (58%) and 11 (42%), males and females, respectively. The mean waist circumference of 97.5 ± 12.43 was significantly related to the fatty liver with a p-value of 0.0001. Waist circumference showed a positive correlation with the frequency of fatty liver on ultrasonography with p-values of 0.000755 (r = 0.590083) and 3.04366E—05 (r = 0.659143523), in males and females, correspondingly. The overall correlation between waist circumference and fatty liver on ultrasonography is statistically significant with a p-value of 4.10503E—08 (r = 0.634737127). Conclusion: One measure used to assess central obesity is waist circumference. In addition, it can also be utilized to assess risk for NAFLD since they are strongly correlated as reported in this study. Waist circumference cut-off values for the Filipinos proposed in this study are the following: >88 cm and >95 cm, in males and females, respectively.

Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.

Pediatric non-alcoholic fatty liver disease:New insights and future directions

One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease(NAFLD),which is the most common form of liver disease in children.NAFLD is defined by hepatic fat infiltration > 5% hepatocytes,as assessed by liver biopsy,in the absence of excessive alcohol intake,viral,autoimmune and drug-induced liver disease.It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis,which,in turn,can evolve into cirrhosis and end stage liver disease.Obesity and insulin resistance are the main risk factors for pediatric NAFLD.In fact,NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome,prediabetes and type 2 diabetes mellitus(T2D).In particular,it has been clearly shown in obese youth that the prevalence of metabolic syndrome,pre-diabetes and type 2 diabetes increaseswith NAFLD severity progression.Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition.Recently,a non-synonymous SNP(rs738409),characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene(PNPLA3),has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children.Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein.The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes,is aimed at acting upon specific targets involved in the pathogenesis.There are some therapeutic approaches that are being studied in children.This article reviews the current knowledge regarding the pediatric fatty liver disease,the new insights and the future directions.

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

Non-alcoholic fatty liver disease(NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance(IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis(NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data(BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR(acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy(the "imperfect" gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention.Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

Non-alcoholic fatty liver disease in 2015

There is worldwide epidemic of non-alcoholic fatty liver disease(NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase.

Pathogenesis and management issues for non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.

Non-alcoholic fatty liver disease and liver transplantation:Outcomes and advances

Non-alcoholic fatty liver disease(NAFLD)is one of the most prevalent causes of chronic liver disease worldwide.In the last decade it has become the third most common indication for liver transplantation in the United States.Increasing prevalence of NAFLD in the general population also poses a risk to organ donation,as allograft steatosis can be associated with non-function of the graft.Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease,although long term outcomes beyond 10 year are lacking.NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted.De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease.Predictors for NAFLD post-transplant recurrence include obesity,hyperlipidemia and diabetes as well as steroid dose after liver transplantation.A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk.Although immunosuppression side effects potentiate obesity and the metabolic syndrome,studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population.Based on pre-transplant data,sustained weight loss through diet and exercise is the most effective therapy for NAFLD.Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents.Studies of these therapies are lacking in the post-transplant population.A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD.

Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease

MicroRNAs(miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAsin alcoholic liver disease(ALD) and non-alcoholic fatty liver disease(NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34 a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.

Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome,which includes hypertension,central obesity,dyslipidemia and insulin resistance.NAFLD includes a wide spectrum of liver alterations,ranging from simple hepatic steatosis to variable degrees of fibrosis,cirrhosis and even hepatocellular carcinoma.Although the etiology and progression of the disorder remain poorly understood,insulin resistance is considered to play a pivotal role in the pathogenesis.Insulin sensitizers such as biguanides,thiazolidinediones(TZDs),glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years.Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase(ALT/AST) levels in the majority of subjects; however,it has no significant effect on liver histology.TZDs improve insulin sensitivity,serum ALT/ AST levels and histology in some cases,but there are some concerns about the safety of long-term therapy.Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are themain points.These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer.The present review provides an overview of insulin sensitizers in the treatment of NAFLD.

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

AIM: To determine characteristics and prognosticpredictors of patients with hepatocellular carcinoma(HCC) in association with non-alcoholic fatty liver disease(NAFLD).METHODS: We reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index(BMI), and the presence of diabetes, hypertension, or dyslipidaemia.RESULTS: Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent(8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of < 25 kg/m2, 25-29 kg/m2 and ≥ 30 kg/m2 respectively. Fifty-nine percent were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤ 1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics(P = 0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of HCC.CONCLUSION: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.

Gut microbiota and non-alcoholic fatty liver disease

BACKGROUND： Non-alcoholic fatty liver disease （NAFLD） is a common disorder with poorly understood pathogenesis. Beyond environmental and genetic factors, cumulative data support the causative role of gut microbiota in disease development and progression.

Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: a review article

Emerging data have highlighted the co-existence of nonalcoholic fatty liver disease(NAFLD) and inflammatory bowel disease; both of which are increasingly prevalent disorders with significant complications and impact on future health burden. Cross-section observational studies have shown widely variable prevalence rates of co-existing disease,largely due to differences in disease definition and diagnostic tools utilised in the studies. Age,obesity,insulin resistance and other metabolic conditions are common risks factors in observational studies. However,other studies have also suggested a more dominant role of inflammatory bowel disease related factors such as disease activity,duration,steroid use and prior surgical intervention,in the development of NAFLD. This suggests a potentially more complex pathogenesis and relationship between the two diseases which may be contributed by factors including altered intestinal permeability,gut dysbiosis and chronic inflammatory response. Commonly used immunomodulation agents pose potential hepatic toxicity,however no definitive evidence exist linking them to the development of hepatic steatosis,nor are there any data on the impact of therapy and prognosis in patient with co-existent diseases. Further studies are required to assess the impact and establish appropriate screening and management strategies in order to allow early identification,intervention and improve patient outcomes.

Treatment options for alcoholic and non-alcoholic fatty liver disease: A review

Alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are serious health problems worldwide.These two diseases have similar pathological spectra,ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma.Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver(simple steatosis),a small percentage develops progressive liver disease.Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available.The treatment for ALD remains as it was 50 years ago:abstinence,nutritional support and corticosteroids(or pentoxifylline as an alternative if steroids are contraindicated).As for NAFLD,the treatment modality is mainly directed toward weight loss and co-morbidity management.Therefore,new pathophysiology directed therapies are urgently needed.However,the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy.Hence,a combination therapy towards multiple targets would eventually be required.In this review,we delineate the treatment options in ALD and NAFLD,including various new targeted therapies that are currently under investigation.We hope that soon we will be having an effective multi-therapeutic regimen for each disease.

Obesity and non-alcoholic fatty liver disease: Disparate associations among asian populations

obesity is a global epidemic contributing to an increas-ing prevalence of obesity-related systemic disorders, including nonalcoholic fatty liver disease. The rising prevalence of nonalcoholic steatohepatitis(NASh) will in the near future lead to end-stage liver disease in a large cohort of patients with NASh-related cirrhosis and NASh is predicted to be a leading indication for liver transplantation in the coming decade. however, the prevalence of obesity and the progression of hepatic histological damage associated with NASh exhibit sig-nificant ethnic disparities. Despite a significantly lower body mass index and lower rates of obesity compared to other ethnic groups, Asians continue to demonstrate a significant prevalence of hypertension, diabetes, met-abolic syndrome and NASh. Ethnic disparities in central adiposity and visceral fat distribution have been hy-pothesized to contribute to these ethnic disparities. The current review focuses on the epidemiology of obesity and NASh among Asian populations.

Vitamin D:A new player in non-alcoholic fatty liver disease?

Vitamin D through its active form 1a-25-dihydroxyvtamin D[1,25(OH)2D]is a secosteroid hormone that plays a key role in mineral metabolism.Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation,cell differentiation and proliferation and inflammation regulation.As our understanding of the many functions of vitamin D has grown,the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide.Concomitantly,non-alcoholic fatty liver disease(NAFLD)has become the most common form of chronic liver disease in western countries.NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors.In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency,as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD.

MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is a multi-faceted condition including simple steatosis alone or associated with inflammation and ballooning(non-alcoholic steatohepatitis) and eventually fibrosis.The NAFLD incidence has increased over the last twenty years becoming the most frequent chronic liver disease in industrialized countries.Obesity,visceral adiposity,insulin resistance,and many other disorders that characterize metabolic syndrome are the major predisposing risk factors for NAFLD.Furthermore,different factors,including genetic background,epigenetic mechanisms and environmental factors,such as diet and physical exercise,contribute to NAFLD development and progression.Several lines of evidence demonstrate that specific microRNAs expression profiles are strongly associated with several pathological conditions including NAFLD.In NAFLD,microRNA deregulation in response to intrinsic genetic or epigenetic factors or environmental factors contributes to metabolic dysfunction.In this review we focused on microRNAs role both as controlled and controllers molecules in NAFLD development and/or their eventual value as non-invasive biomarkers of disease.

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome

AIM: To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis(NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH.METHODS: This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome(Met S) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients receivedlifestyle advice and were treated for a 12 mo period with rosuvastatin(10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid(SUA), high sensitivity C reactive protein(hs CRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values.RESULTS: The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20 th, which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3rd treatment month(ANOVA P < 0.001), while alkaline phosphatase activities by the 6th treatment month(ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced(P < 0.001). Lipid values were normalised by the 3rd treatment month. No patient had Met S by the 9th treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group.CONCLUSION: These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve Met S within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

Mechanism of action of gypenosides on type 2 diabetes and non-alcoholic fatty liver disease in rats

AIM:To explore the mechanism of action of gypenosides(GPs)on type 2 diabetes mellitus and non-alcoholic fatty liver disease(T2DM-NAFLD)in rats.METHODS:Sixty rats were randomly divided into a healthy group,an untreated disease model group andGP-treatment groups.The study involved the evaluation of biochemical parameters,including serum aspartate transaminase(AST),alanine transferase(ALT),blood glucose(BG),triglycerides(TG)and total cholesterol(TC).Additionally,the protective effect of the treatments were confirmed histopathologically and the expression of TNF-αand NF-κB in the rat liver was analyzed using immunohistochemistry.The expression of proliferatoractivated receptor gamma(PPARγ)and cytochrome P450(CYP450)1A1 m RNA was determined by quantitative RTPCR.RESULTS:GP treatments at oral doses of 200,400,and800 mg/kg per day significantly decreased the levels of serum AST and ALT(P<0.05,P<0.01),especially at the dose of 800 mg/kg per day.To a similar extent,GP at800 mg/kg per day reduced the levels of BG(4.19±0.47,P<0.01),TG(80.08±10.05,P<0.01),TC(134.38±16.39,P<0.01)and serum insulin(42.01±5.04,P<0.01).The expression of TNF-αand NF-κB measured by immunohistochemistry was significantly reduced by GPs in a dose-dependent manner,and the expression of PPARγand CYP4501A1 m RNA,as measured using quantitative real-time PCR,were significantly down-regulated by GPs.Moreover,GPs decreased the infiltration of liver fats and reversed the histopathological changes in a dosedependent manner.CONCLUSION:This study suggests that GPs have a protective effect against T2DM-NAFLD by down-regulating the expression of TNF-αand NF-κB proteins,and PPARγand CYP4501A1 m RNAs.