Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years

Background and Aim: Although nonalcoholic fatty liver disease (NAFLD) is very common among morbidly obese patients, the effect of weight loss after bariatric surgery on inflammation and fibrosis related to NAFLD is still a matter of debate. The aim of this study was to evaluate the impact of Roux‐en‐Y gastric bypass (RYGB) surgery on NAFLD with a follow up of 2 years. Methods: Eighteen consecutive NAFLD patients with body mass index >40 kg/m² undergoing gastroplasty with RYGB were enrolled, and wedge liver biopsy was obtained at the operation. After 2 years, these patients underwent percutaneous liver biopsy. Results: At baseline, 67% of patients had nonalcoholic steatohepatitis (NASH) and 33% had steatosis, according to the NASH Clinical Research Network Scoring System (NAS) for biopsy. Cirrhosis was present in 5.5% of the patients with NASH. After a mean excess weight loss of 60%, steatosis disappeared in 84% and fibrosis disappeared in 75% of the patients. Hepatocellular ballooning disappeared in 50%. A slight lobular inflammatory infiltrate remained in 81%, apparently unrelated to fatty degeneration. As liver biochemical variables had been found within normal limits in 92.3% of patients at initial biopsy, no difference was found 2 years later. Lipid profile and blood sugar plasma concentration were closer to normal in all patients after 2 years (P < 0.05). Conclusions: Aspects of NAFLD including steatohepatitis improved significantly with massive weight loss at 2 years after RYGB surgery. No patient in this series had progression of hepatic fibrosis.     

Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes

CONTEXT: Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels. OBJECTIVE: Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. DESIGN AND METHODS: Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss. SETTING: This outpatient study was conducted at the General Clinical Research Center. MAIN OUTCOME MEASURES: Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load. RESULTS: At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 +/- 6 to 112 +/- 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 +/- 27.5 to 44.8 +/- 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP. CONCLUSIONS: These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.     

Hepatic ratio of phosphatidylcholine to phosphatidylethanolamine predicts survival after partial hepatectomy in mice

A major predictor of failed liver resection and transplantation is nonalcoholic fatty liver disease (NAFLD). NAFLD is linked to a wide spectrum of diseases including obesity and diabetes that are increasingly prevalent in Western populations. Thus, it is important to develop therapies aimed at improving posthepatectomy outcomes in patients with NAFLD, as well as to improve the evaluation of patients slated for hepatic surgery. Decreased hepatic phosphatidylcholine (PC) content and decreased ratio of hepatic PC to phosphatidylethanolamine (PE) have previously been linked to NAFLD. To determine if decreased hepatic PC/PE could predict survival after hepatectomy, we used mouse models lacking key enzymes in PC biosynthesis, namely, phosphatidylethanolamine N-methyltransferase and hepatic-specific CTP:phosphocholine cytidylyltransferase α. These mice were fed a high-fat diet to induce NAFLD. We then performed a 70% partial hepatectomy and monitored postoperative survival. We identified hepatic PC/PE to be inversely correlated with the development of steatosis and inflammation in the progression of NAFLD. Decreased hepatic PC/PE before surgery was also strongly associated with decreased rates of survival after partial hepatectomy. Choline supplementation to the diet increased hepatic PC/PE in Pemt(-/-) mice with NAFLD, decreased inflammation, and increased the survival rate after partial hepatectomy. Conclusion: Decreased hepatic PC/PE is a predictor of NAFLD and survival following partial hepatectomy. Choline supplementation may serve as a potential therapy to prevent the progression of NAFLD and to improve postoperative outcome after liver surgery.     

Recent advances in dietary supplementation,in treating non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently known as the most common liver problem, characterized by excessive lipid accumulation in hepatocytes,which may progress to other liver diseases such as nonalcoholic steatohepatitis, hepatic tissue fibrosis, livercirrhosis, and failure or hepatocellular carcinoma. Since NAFLD is positively associated with the development of obesity, insulin resistance, and ultimately type 2 diabetes mellitus, it is often regarded as the hepatic manifestation of the metabolic syndrome. No pharmacologic treatment has yet been proven for this disease. For most patients with presumed or confirmed NAFLD, the only proven strategy is to offer lifestyle advice that can lead to sustained weight loss. Since insulin resistance, oxidative stress, inflammation, and necro-apoptosis are involved in NAFLD pathogenesis, it seems that every potential therapeutic agent should target one or some of these pathologic events. There are many well known anti-oxidants, anti-inflammatory, and insulin sensitizer dietary supplements which have shown beneficial effects on NAFLD improvement in animal and human studies. The purpose of this review is to explore the existing evidences on dietary supplements considered to have hepatoprotective properties, and to present some proposed mechanisms by which they may protect against NAFLD.     

Risk factors associated with nonalcoholic fatty liver disease and its relationship with the hepatic histological changes

OBJECTIVE: The objective of this study is to determine the association between risk factors and nonalcoholic fatty liver disease (NAFLD), and to establish the relationship between risk factors and hepatic histological changes in obese women. METHODS: A case-control design study. Women with NAFLD (cases) were compared with a control group of obese women without NAFLD matched by age, body mass index, waist circumference, and body fat. Irrespective of serum aminotransferases levels, diagnosis of NAFLD was established by the presence of type II diabetes, hypertriglyceridemia, and ultrasonographic changes of hepatic steatosis. Diagnosis of nonalcoholic steatohepatitis was performed by a liver biopsy. Women with an aspartate aminotransferase/alanine aminotransferase (ALT) ratio of at least 1 underwent liver biopsy. Alcohol consumption, hepatitis, and drugs that promote cholestasis or liver injury were the exclusion criteria. Multiple regression analysis was used to compute the association between the risk factors and NAFLD, and Spearman's analysis was used to examine its relationship with histological hepatic changes. RESULTS: A total of 108 obese women were enrolled. The frequency of high blood pressure, hypertriglyceridemia, and diabetes was similar between the groups. ALT (54.4+/-33.3 and 39.8+/-29.8, P=0.03) but not aspartate aminotransferase (45.4+/-23.1 and 36.7+/-21.2, P=0.06) was significantly higher in the women with NAFLD. The multivariate regression analysis showed a significant association of ALT (odds ratio 2.7; 95% confidence interval, 1.3-10.4), but not other variables with NAFLD. Type II diabetes was strongly correlated with ballooning and inflammation, and ALT with inflammation and fibrosis. CONCLUSION: Obese women with similar metabolic alterations exhibit different hepatic outcomes. Elevation of ALT, but not other risk factors, was associated with NAFLD. Diabetes and ALT correlate with histological hepatic changes.     

Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation

BACKGROUND: The alpha isotype of actin expressed by hepatic stellate cells reflects their activation to myofibroblast-like cell and has been directly related to experimental liver fibrogenesis, and indirectly to human fibrosis in chronic liver disease. AIMS: To evaluate the changes in distribution and percentage of alpha-smooth muscle actin-positive hepatic stellate cells and the correlation with the degree of the fibrosis in cirrhotic livers, as well as in patients with recurrent HCV chronic hepatitis after liver transplantation. METHODS: Human liver biopsies were divided in four groups: (1) normal livers obtained from cadaveric liver donors (n=35), (2) cirrhosis post-HBV hepatitis (n=11), (3) cirrhosis post-HCV hepatitis (n=10), and (4) post-transplant recurrent HCV chronic hepatitis (n=13). Samples were stained with anti-alpha-smooth muscle actin antibody by immunoperoxidase method and semi-quantitatively evaluated. Liver fibrosis was assessed from specimens stained with Masson's trichrome and quantified by computer image analysis. RESULTS: The percentage of alpha-smooth muscle actin-positive hepatic stellate cells was significantly higher in the HBV cirrhosis, HCV cirrhosis and post-transplant HCV recurrent hepatitis groups (36.1+/-15.2, 23.8+/-19.7 and 27.8+/-16.4%, respectively) compared to the liver donor group (2.9+/-4.0%). The alpha-smooth muscle actin-positive hepatic stellate cells to fibrous tissue ratio were significantly higher in the post-transplant recurrent HCV hepatitis group (2.36+/-1.12) compared to both the donor livers and the HCV cirrhosis groups (0.74+/-1.09 and 1.03+/-0.91, respectively). The alpha-smooth muscle actin-positive hepatic stellate cell percentage and fibrosis correlated positively in the post-transplant recurrent HCV hepatitis group and negatively in the HCV cirrhosis group. No difference in the immunohistochemical and morphometrical variables was found between the HCV cirrhosis and HBV cirrhosis groups. CONCLUSIONS: These results indirectly confirm that, in vivo, alpha-smooth muscle actin expression is a reliable marker of hepatic stellate cells activation which precedes fibrous tissue deposition even in the setting of recurrent HCV chronic hepatitis after liver transplantation, and it could be useful to identify the earliest stages of hepatic fibrosis and monitoring the efficacy of the therapy. In the presence of advanced cirrhosis other factors, rather than alpha-smooth muscle actin-positive hepatic stellate cells, may sustain fibrosis deposition.     

The effects of weight loss on normal transaminase levels in obese patients

BACKGROUND: Obesity is associated with insulin resistance, which is the main pathogenic factor for nonalcoholic fatty liver disease (NAFLD). NAFLD can progress without associated elevations in liver enzymes. Therefore, we investigated the effects of weight loss on normal transaminase levels in obese subjects who are at risk for NAFLD. METHODS: Thirty-seven obese patients with normal ALT levels were evaluated. All patients received an individualized low-calorie diet over at least 6 months. Twenty-two patients who achieved weight loss of at least 5% body weight were identified as the study group and the others as the control group. Transaminases, insulin resistance, and body mass index were compared before and after the intervention. RESULTS: Hepatic steatosis was found in 83.8% of obese patients. ALT was correlated with HOMA-IR in all patients at baseline (r = 0.363, P = 0.027). At the end of the follow-up, mean weight loss achieved in the study and control groups were 9.2% (8.7 +/- 3.0 kg) and 0.3% (0.5 +/- 2.8 kg), respectively. In the study group, HOMA-IR and ALT decreased from 4.0 +/- 1.8 to 2.4 +/- 0.9 and from 21.4 +/- 6.6 IU/L to 16.8 +/- 5.5 IU/L, respectively (P = 0.005 and P = 0.044). CONCLUSIONS: The results demonstrate that weight loss results in a decrease in normal ALT levels as well as insulin resistance. Therefore, the normal range for ALT may need to be reassessed.     

Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese

BACKGROUND/AIMS: Insulin resistance and systemic hypertension are predictors of advanced fibrosis in obese patients with non-alcoholic fatty liver disease (NAFLD). Genetic factors may also be important. We hypothesize that high angiotensinogen (AT) and transforming growth factor-beta1 (TGF-beta1) producing genotypes increase the risk of liver fibrosis in obese subjects with NAFLD. METHODS: One hundred and five of 130 consecutive severely obese patients having a liver biopsy at the time of laparoscopic obesity surgery agreed to have genotype analysis. Influence of specific genotype or combination of genotypes on the stage of hepatic fibrosis was assessed after controlling for known risk factors. RESULTS: There was no fibrosis in 70 (67%), stages 1-2 in 21 (20%) and stages 3-4 fibrosis in 14 (13%) of subjects. There was no relationship between either high AT or TGF-beta1 producing genotypes alone and hepatic fibrosis after controlling for confounding factors. However, advanced hepatic fibrosis occurred in five of 13 subjects (odds ratio 5.7, 95% confidence interval 1.5-21.2, P=0.005) who inherited both high AT and TGF-beta1 producing polymorphisms. CONCLUSIONS: The combination of high AT and TGF-beta1 producing polymorphisms is associated with advanced hepatic fibrosis in obese patients with NAFLD. These findings support the hypothesis that angiotensin II stimulated TGF-beta1 production may promote hepatic fibrosis.     

Association of hepatic iron deposition and serum iron indices with hepatic inflammation and fibrosis stage in nonalcoholic fatty liver disease]

BACKGROUND/AIMS: Nonalcoholic steatohepatitis can develop from nonalcoholic fatty liver and progress to severe liver disease such as cirrhosis. The mechanism determining the progression from fatty liver to steatohepatitis is unknown. Iron is suspected to enhance hepatic damage associated with nonalcoholic fatty liver disease (NAFLD). The aims of this study were to evaluate the relationship of serum iron indices and hepatic iron deposition with hepatic fibrosis or inflammation, and to assess whether the increased hepatic iron deposition is an independent predictor of progression to liver injury. METHODS: The biochemical and histopathological data of thirty-nine patients with NAFLD were analyzed. Liver biopsy findings were graded according to the method described by Brunt, et al. Hepatic iron concentration was available in 29 of 39 patients. RESULTS: The mean hepatic iron concentration and hepatic iron indices were 1,349+/-1,188 microg/g dry weight and 0.9+/-0.7 microg/g/age. Serum ferritin and body mass indices were associated with hepatic inflammation (p=0.001, p=0.006) and fibrosis (p=0.005, p=0.013). Hepatic iron concentration and hepatic iron index were not associated with hepatic inflammation and fibrosis. Multivariate analysis did not identify serum ferritin or body mass index as an independent predictor of liver injury. CONCLUSIONS: Hepatic iron deposition shows no association with the degree of hepatic inflammation or fibrosis. Hepatic iron is not an independent predictor of hepatic injury in patients with NAFLD.     

Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease

OBJECTIVES: To explore associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND PATIENTS: In a cross-sectional study, we enrolled 60 consecutive NAFLD patients and 60 age-, sex- and body mass index (BMI)-matched healthy controls. MEASUREMENTS: NAFLD (by liver biopsy), plasma adiponectin concentrations, insulin resistance (by homeostasis model assessment, HOMA-IR) and metabolic syndrome (MetS) features. RESULTS: NAFLD patients had a marked decrease in plasma adiponectin concentration (6.1 +/- 2.8 vs. 13.6 +/- 3.8 microg/ml, P < 0.001) compared with matched controls. MetS, as defined by the Adult Treatment Panel III (ATP III) criteria, and its individual components were more frequent among NAFLD patients. The marked differences in adiponectin concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, HOMA-IR score and MetS components. Notably, decreased adiponectin levels were closely associated with the degree of hepatic steatosis, necroinflammation and fibrosis (P < 0.001 for all) among NAFLD patients. By logistic regression analysis, low adiponectin levels independently predicted hepatic steatosis [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.5-5.8, P < 0.001] and necroinflammation (OR 3.1, 95% CI 1.9-7, P < 0.001), but not fibrosis (P = 0.07), after adjustment for age, sex, BMI, HOMA-IR and MetS components. CONCLUSIONS: NAFLD patients have markedly lower plasma adiponectin concentrations than control subjects. Low adiponectin levels are strongly associated with the severity of liver histology, thus further supporting the hypothesis that adiponectin might be involved in the development of NAFLD.     

Hepatic alpha-smooth muscle actin expression in hepatitis C patients before and after interferon therapy

BACKGROUND/AIMS: The mechanism of hepatic fibrogenesis with chronic viral hepatitis is not well understood. Persistent activation of hepatic stellate cells is felt to play a role in the development of fibrogenesis and progression to cirrhosis. METHODOLOGY: We determined the expression of hepatic alpha-smooth muscle actin, a marker of hepatic stellate cell activation, in 29 patients with chronic hepatitis C and varying degrees of liver injury and fibrosis. In addition to a baseline evaluation, we assessed the effect of interferon therapy on alpha-smooth muscle actin expression in 11 patients, including 6 with a sustained response to therapy. Specimens were evaluated by light microscopy for grade of inflammation and stage of fibrosis. Expression of alpha-smooth muscle actin was assessed semiquantitatively by immunohistochemical staining. RESULTS: At baseline, all patients had alpha-smooth muscle actin expressed within the liver without an obvious correlation with the severity of liver injury. However, among sustained responders, a reduction in hepatic necroinflammatory activity was associated with a trend towards a decrease in alpha-smooth muscle actin expression. This however did not reach statistical significance. CONCLUSIONS: Hepatic alpha-smooth muscle actin expression, as a marker of hepatic stellate cell activation appears reversible and tends to correlate with necroinflammatory activity.     

Ameliorative effects of lutein on non-alcoholic fatty liver disease in rats

AIM: To investigate the therapeutic effects of lutein against non-alcoholic fatty liver disease(NAFLD) and the related underlying mechanism.METHODS: After 9 d of acclimation to a constant temperature-controlled room(20 ℃-22 ℃) under 12h light/dark cycles,male Sprague-Darley rats were randomly divided into two groups and fed a standard commercial diet(n = 8) or a high-fat diet(HFD)(n = 32) for 10 d.Animals receiving HFD were then randomly divided into 4 groups and administered with 0,12.5,25,or 50 mg/kg(body weight) per day of lutein for the next 45 d.At the end of the experiment,the perinephric and abdominal adipose tissues of the rats were isolated and weighed.Additionally,serum and liver lipid metabolic condition parameters were measured,and liver function and insulin resistance state indexes were assessed.Liver samples were collected and stained with hematoxylin eosin and Oil Red O,and the expression of the key factors related to insulin signaling and lipid metabolism in the liver were detected using Western blot and real-time polymerase chain reaction analyses.RESULTS: Our data showed that after being fed a high-fat diet for 10 d,the rats showed a significant gain in body weight,energy efficiency,and serum total cholesterol(TC) and triglyceride(TG) levels.Lutein supplementation induced fat loss in rats fed a highfat diet,without influencing body weight or energy efficiency,and decreased serum TC and hepatic TC and TG levels.Moreover,lutein supplementation decreased hepatic levels of lipid accumulation and glutamic pyruvic transaminase content,and also improved insulin sensitivity.Lutein administration also increased the expression of key factors in hepatic insulin signaling,such as insulin receptor substrate-2,phosphatidylinositol 3-kinase,and glucose transporter-2 at the gene and protein levels.Furthermore,high-dose lutein increased the expression of peroxisome proliferators activated receptor-α and sirtuin 1,which are associated with lipid metabolism and insulin signaling.CONCLUSION: These results demonstrate that lutein has positive effects on NAFLD via the modulation of hepatic lipid accumulation and insulin resistance.     

Recent concepts in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors, including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however, staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as cirrhosis and hepatocellular carcinoma, which occur in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.     

The metabolic triad of non-alcoholic fatty liver disease,visceral adiposity and type 2 diabetes: Implications for treatment

Non-alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non-alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP or GLP-1/glucagon receptor co-agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan-PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.     

GLP‐1 receptor agonists: effects on the progression of non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and its incidence has been increasing recently. In addition to hepatic complications, NAFLD is also recognized as an independent risk factor for cardiovascular disease. Unfortunately, the current therapies for NAFLD display variable efficacy; a novel and effective drug is urgently needed. Glucagon‐like peptide‐1 (GLP‐1), a receptor agonist is a new drug approved for treating type 2 diabetes. Recently, these types of agents have shown a novel therapeutic effect on NAFLD. However, the mechanisms of GLP‐1 receptor agonists on the treatment of NAFLD have not yet been explained precisely. Recent studies have demonstrated that GLP‐1 reverses the progression of NAFLD not only indirectly through an incretin effect that improves key parameters involved in NAFLD, but also a direct effect on lipid metabolism of hepatocytes and inflammation in liver. In this review, we provided an overview of the role and mechanisms of GLP‐1 in the therapy of NAFLD. Copyright © 2014 John Wiley & Sons, Ltd.     

Glycosylphosphatidylinositol-specific phospholipase d in nonalcoholic Fatty liver disease: a preliminary study

CONTEXT: Recent studies demonstrated that de novo lipogenesis is increased in patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD also have plasma lipid abnormalities. These lipid abnormalities may in part be related to insulin resistance, which is common in patients with NAFLD. Insulin resistance is associated with alterations in proteins involved in lipid metabolism including glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), which is involved in triglyceride metabolism. OBJECTIVE: The objective of the study was to determine whether alterations in serum and hepatic levels of GPI-PLD occur in patients with NAFLD. DESIGN AND PATIENTS: We examined the following: 1) levels of serum GPI-PLD in nondiabetics with nonalcoholic steatohepatitis, compared with matched controls; 2) hepatic expression of GPI-PLD mRNA in patients with normal liver or NAFLD; and 3) effect of overexpressing GPI-PLD vs. beta-galactosidase (control) on global gene expression in a human hepatoma cell line. RESULTS: The serum levels of GPI-PLD were significantly higher in patients with nonalcoholic steatohepatitis than in matched controls (119 +/- 24 vs.105 +/- 15 microg/ml, P = 0.047). The hepatic expression of GPI-PLD mRNA was increased nearly 3-fold in NAFLD patients, compared with patients with normal liver (3.1 +/- 2.6 vs. 1.1 +/- 1.0 arbitrary units per microgram total RNA, P = 0.026). Finally, overexpressing GPI-PLD was associated with an increase in de novo lipogenesis genes. CONCLUSIONS: Patients with NAFLD have elevated serum levels and hepatic expression of GPI-PLD, and its overexpression in vitro is associated with increased expression of de novo lipogenesis genes. These results suggest that GPI-PLD may play a role in the pathogenesis of NAFLD and/or its metabolic features and warrants further investigation.     

Metabolic fate of extrahepatic arginine in liver after burn injury

Increased nitrogen loss in the form of urea is a hallmark of the metabolic aberrations that occur after burn injury. As the immediate precursor for urea production is arginine, we have conducted an investigation on the metabolic fate of arginine in the liver to shed light on the metabolic characteristics of this increased nitrogen loss. Livers from 25% total surface burn (n = 8) and sham burn rats (n = 8) were perfused in a recycling fashion with a medium containing amino acids and stable isotope labeled l-[(15) N(2)-guanidino, 5,5-(2)H(2)]arginine for 120 minutes. The rates of glucose and urea production and oxygen consumption were measured. The rate of unidirectional arginine transport and the intrahepatic metabolic fate of arginine in relation to urea cycle activity were quantified by tracing the disappearance rate of the arginine tracer from and the appearance rate of [(15)N(2)]urea in the perfusion medium. Perfused livers from burned rats showed higher rates of total urea production (mean +/- SE, 4.471 +/- 0.274 v 3.235 +/- 0.261 mumol. g dry liver(-1). min(-1); P <.01). This was accompanied by increased hepatic arginine transport (1.269 +/- 0.263 v 0.365 +/- 0.021 mumol. g dry liver(-1). min(-1)) and an increased portion of urea production from the transported extrahepatic arginine (12.9% +/- 2.9% v 3.5% +/- 0.4%, P <.05). The disposal of arginine via nonurea pathways was also increased (0.702 +/- 0.185 v 0.257 +/- 0.025 mumol/g dry weight(-1)/min(-1); P <.05). We propose that increased inward transport and utilization of extrahepatic arginine by the liver contributes to the accelerated urea production after burn injury and accounts, in part, for its conditional essentiality in the nutritional support of burn patients.     

胰高血糖素样肽-1改善非酒精性脂肪性肝病作用机制研究进展*

近期研究表明,胰高血糖素样肽-1受体激动剂可从改善肝细胞脂质代谢、抑制炎症反应、调节细胞自噬等多个环节减轻非酒精性脂肪性肝病（NAFLD）患者肝脏脂质沉积,改善组织学损伤,有望成为治疗NAFLD药物的新选择。     

Weight loss interventions and nonalcoholic fatty liver disease: Optimizing liver outcomes

The growth in prevalence of obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) has become one of the most important global health challenges. The three chronic diseases are closely linked in their epidemiology and pathophysiology. Currently, weight loss is the most effective treatment for NAFLD (even in the minority of patients with NAFLD who do not have obesity) and is recommended in all national and international guidelines. Accumulating evidence has shown that weight loss, whether achieved by diet and lifestyle interventions, bariatric surgery or pharmacotherapy, can improve biomarkers of NAFLD, as well as prevent progression and, in some cases, reverse fibrosis. There is a dose dependency of weight loss with NAFLD improvement. Pharmacotherapy with antiobesity medications, alone or in combination with intensive lifestyle interventions or other weight-loss drugs, is closing the efficacy gap between diet and exercise and weight-loss surgery in efficacy at reversing obesity. Given the importance of providing effective weight-loss treatment to patients with NAFLD, weight management services need to be made increasingly available and embedded within hepatology services. This narrative review addresses the evidence that weight loss optimizes liver outcomes in people with NAFLD.     

长链非编码RNA EXOC7在非酒精性脂肪性肝病中的表达及临床意义

目的 观察非酒精性脂肪性肝病(NAFLD)患者血清及肝穿刺组织中长链非编码RNA(lncRNA)EXOC7的表达及临床意义。方法 选取2013年1月1日-2018年12月31日于西南医科大学附属医院住院行肝穿刺并经影像学及组织病理学诊断为NAFLD的患者120例,其中非酒精性单纯性脂肪肝(NAFL)47例,非酒精性脂肪性肝炎(NASH)73例。另选取同期体检的50例无脂肪变性和脂肪性肝炎的其他肝病患者作为对照组。采用Real-time PCR法检测lncRNA EXOC7在肝组织及血清中的表达。计量资料两组间比较采用t检验;多组间比较采用方差分析,进一步两两比较采用SNK-q检验。计数资料两组间比较采用χ2检验。采用Pearson相关分析lncRNA EXOC7表达与临床各生化指标的关系。绘制受试者工作特征曲线(ROC曲线)并分析lncRNA EXOC7的临床诊断价值。结果 与对照组相比,NAFL和NASH患者的组织及血清中lncRNA EXOC7表达显著增高(P值均<0.05),且其表达水平随着肝脏脂肪变性及炎症程度的加重而提升(F=19.96,P<0.05)。相关性分析结果显示,lncRNA EXOC7表达与TG、LDL-C呈正相关(r值分别为0.785、0.847,P值均<0.001);而与HDL-C、胰岛素敏感指数呈负相关(r值分别为-0.726、-0.709,P值均<0.001)。lncRNA EXOC7诊断NAFLD的ROC曲线下面积为0.812(95%可信区间:0.599~0.915,P<0.001),敏感度为85.42%,特异度为81.17%。结论 lncRNA EXOC7在NAFLD患者中高表达,并随脂肪变性及炎症程度的加重而升高,提示lncRNA EXOC7可能是NAFLD防治的潜在新靶点。