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Multiple Effects of Prostaglandin I2-IP Signaling in the Later Phase of Nonalcoholic Steatohepatitis
AGA Abstracts
range=20-74) months. After adjusting for age, NOFLD patients had an 18% increased risk of mortality compared to non-obese patients without fatty liver (p=0.056). Obese-FLD patients had a 24% increased risk of mortality compared to non-obese subjects without fatty liver (p=0.006), Figure. The most common cause of mortality in NOFLD was cardiovascular events accounting for 137/584 (23.5%) of deaths. Factors most associated (p<0.0001) with increased mortality in NOFLD were a history of coronary artery disease (HR=6.88), increased Cystatin-C (HR=6.26), increased serum creatinine (HR=3.75), larger waist circumference (HR=2.72), glucose intolerance (HR=2.59), and hypertension (HR=2.50). Modest alcohol consumption was associated with a 46% decreased risk of mortality when compared with those who abstained from alcohol within the NOFLD population (p<0.0001). Conclusions: In the absence of risk factors, NOFLD per se is not associated with a significantly increased overall mortality compared to lean population without fatty liver. Patients with FLD may benefit from modest alcohol consumption.
Figure 2. BPS drastically decreased the occurrence of hepatic tumors in WT mice.
Mo1458 ARE THERE DIFFERENT PREDICTORS OF MORTALITY IN LEAN AND OBESE/OVERWEIGHT PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)? Pegah Golabi, Munkhzul Otgonsuren, Daisong Tan, Leyla de Avila, Cameron T. Locklear, Natsu Fukui, Aimal Arsalla, Trevor Gogoll, Zobair M. Younossi Introduction: NAFLD is associated with cirrhosis and its complications. Although most patients with NAFLD are overweight and obese, some NAFLD patients are considered lean. Aim: Our aim was to compare the long-term outcome of lean patients with NAFLD to overweight/obese NAFLD patients. Methods: The National Health and Nutrition Examination Survey-III (NHANES-III) (1988-1994) was used for this study. The study cohort was followed through 31 December 2011 via linkage to the National Death Index. The Underlying Cause of Death 113 codes were used to establish causes of death. NAFLD was defined by presence of hepatic steatosis by ultrasound in the absence of other causes of liver disease. Individuals were classified according to their BMIs as lean (BMI<25), overweight (BMI 25-30) and obese (BMI>30). Data were analyzed in (1) lean and (2) obese/overweight cohorts, separately. Allcause mortality and hazard ratios with 95% confidence intervals (CI) were estimated by Cox proportional hazard models. All statistical tests were conducted in SAS version 9.3 and considered significant when two-sided p was <0.05. Results: Among 10,563 NHANES participants who qualified the criteria for the study, the prevalence of NAFLD was 22.7% (n= 2,397). Of NAFLD patients, 18% was lean and 82% was overweight/obese. The proportions of NAFLD patients with components of metabolic syndrome and cardiovascular diseases were higher in the overweight/obese NAFLD group than the lean NAFLD group. During 24 years follow up, there were 2,324 deaths (226,080 person-years). Overall mortality ratio was higher in the overweight/obese NAFLD group [26% (40,164 person-years)] than the lean NAFLD group [16% (8,964 person-years)]. The most common cause of death were (29%) cardiovascular diseases in the obese/overweight cohort while malignancy was the most common cause of death in the lean group(28%). Nevertheless, multivariate analysis revealed that in both groups, age, smoking history, presence of cardiovascular diseases and Index of NASH (ION) scores≥50 were independent predictors of overall mortality. On the other hand, presence of NAFLD by ultrasound was the independent predictor of overall mortality only in lean cohort. Conclusions: Overweight or obesity NAFLD have higher rates of mortality. On the other hand, presence of NAFLD is also associated with overall mortality only in lean subjects.
Figure
Mo1457 MULTIPLE EFFECTS OF PROSTAGLANDIN I2-IP SIGNALING IN THE LATER PHASE OF NONALCOHOLIC STEATOHEPATITIS Shima Kumei, Toshikatsu Okumura, Fumitaka Ushikubi ABSTRUCT: Nonalcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and it has become a global health issue. NAFLD is divided into two categories, benign simple steatosis and nonalcoholic steatohepatitis (NASH). In the later phase of NASH, cirrhosis and hepatocellular carcinoma often develop. Although earlier investigators found that cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoids biosynthesis, is up-regulated in the liver of NASH patients, a role of prostanoids in the development of NASH remains to be determined. Previously we showed that prostaglandin (PG) I2 signaling has suppressive effects in animal NASH model using PGI2 receptor IP knock-out (IP-KO) mice, which had earlier development of NASH with augmented steatosis, severe inflammatory cell infiltration and greater oxidative stress. In addition, an IP agonist showed a potent protective effect against hepatic inflammation by reducing the number of infiltrating F4/80-positive cells. However, the effect of PGI2-IP signaling on hepatic fibrosis and carcinogenesis has not been elucidated yet. AIM: The purpose of this study was to clarify whether PGI2-IP signaling exerts a protective action in the later phase of NASH. METHODS: A methionine- and choline-deficient diet (MCDD) or a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) was used for the evaluation of fibrosis and carcinogenesis, respectively. Beraprost (BPS), a specific IP agonist, was administrated orally to mice every day during the experimental periods. RESULTS: BPS successfully suppressed hepatic fibrosis in WT liver with the decreased hepatic mRNA expression levels of collagen Iα1 and tumor growth factor (TGF) β (Figure 1). Moreover, BPS drastically decreased the occurrence of hepatic tumors in WT mice (Figure 2). CONCLUSIONS: We clarified that PGI2-IP signaling has suppressive effects on the development of fibrosis and carcinogenesis in the later phase of NASH. We speculate that an IP agonist could be a potent therapeutic tool for NASH.
Mo1459 INDUCIBLE NITRIC OXIDE SYNTHASE IS INDEPENDENTLY ASSOCIATED WITH THE INCREASED HEPATIC STEATOSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) Elzafir Elsheikh, James M. Estep, Sean Felix, Hussain Allawi, Thomas Jeffers, Zahra Younoszai, Pegah Golabi, Kourosh Kalachi, Bashir Noor, Daisong Tan, Munkhzul Otgonsuren, Andrei Racila, Brian P. Lam, Jason Poff, Lynn Gerber, Zobair M. Younossi Background and Aim: NAFLD is a common cause of liver disease commonly associated with cardiovascular diseases (CVD). Hepatic steatosis is independently associated with CVD mortality. Inducible nitric oxide synthase (iNOS) is associated with CVD. In healthy livers, inducible nitric oxide synthase (iNOS) is not expressed. However, it is readily upregulated in the liver under pathological conditions. Little is known about the role of iNOS, a source of reactive nitrogen species, in NAFLD. Our aim was to assess the level of iNOS and NO synthase inhibitor [Asymmetric dimethylarginine (ADMA)] in patients with NAFLD. Methods: The study cohort consisted of 146 NAFLD patients. Each patient had fasting serum, clinical data and abdominal ultrasound. NAFLD was defined as radiologic fatty liver in the absence of other causes of liver disease and excessive alcohol use. Right kidney echogenicity was used for determination of liver parenchyma echogenicity. Hepatic steatosis was scored from 0 to 6 points by the study radiologist according to a standard protocol. A score of >2 was considered significant hepatic steatosis. iNOS (pg/mL) and ADMA (ng/mL) concentrations were determined in the fasting serum using by ELISA. Whole blood was used to genotype patients for a non-synonymous (S->L) single nucleotide polymorphism (SNP) of iNOS, rs2297518, by TaqMan genotyping assays. Results: iNOS levels were higher in NAFLD patients with significant hepatic steatosis as compared to patients with lower scores for hepatic steatosis (median 990 pg/mL vs median 903 pg/mL, p<0.01). NAFLD patients in >25th quartile of iNOS levels (>363 pg/ml) had the increased risk of significant hepatic steatosis [OR: 4.59 (95% CI: 1.93-10.9)]. In multivariate analysis, iNOS [OR: 6.98 (95% CI: 1.98-24.6)] and obesity (BMI >30 kg/m2) [OR: 2.80 (95% CI: 1.10-7.10)] were independently associated with increased risk for significant hepatic steatosis. Pairwise comparison showed significant enrichment of rs2297518 minor alleles in the "significant steatosis" patient population (P=0.02). Additionally, iNOS polymorphism was correlated with significant hepatic steatosis (OR 95% CI = 2.7 (1.3-5.8), P = 0.01). Interestingly, circulating iNOS
Figure 1. Hepatic mRNA expression levels of Collagen Iα1 and TGF β Values are expressed as means ± SEM.†P <0.05 vs. the corresponding WT mice fed normal diet *P <0.05 vs. the corresponding WT mice fed MCDD
AGA Abstracts
S-684
range=20-74) months. After adjusting for age, NOFLD patients had an 18% increased risk of mortality compared to non-obese patients without fatty liver (p=0.056). Obese-FLD patients had a 24% increased risk of mortality compared to non-obese subjects without fatty liver (p=0.006), Figure. The most common cause of mortality in NOFLD was cardiovascular events accounting for 137/584 (23.5%) of deaths. Factors most associated (p<0.0001) with increased mortality in NOFLD were a history of coronary artery disease (HR=6.88), increased Cystatin-C (HR=6.26), increased serum creatinine (HR=3.75), larger waist circumference (HR=2.72), glucose intolerance (HR=2.59), and hypertension (HR=2.50). Modest alcohol consumption was associated with a 46% decreased risk of mortality when compared with those who abstained from alcohol within the NOFLD population (p<0.0001). Conclusions: In the absence of risk factors, NOFLD per se is not associated with a significantly increased overall mortality compared to lean population without fatty liver. Patients with FLD may benefit from modest alcohol consumption.
Figure 2. BPS drastically decreased the occurrence of hepatic tumors in WT mice.
Mo1458 ARE THERE DIFFERENT PREDICTORS OF MORTALITY IN LEAN AND OBESE/OVERWEIGHT PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)? Pegah Golabi, Munkhzul Otgonsuren, Daisong Tan, Leyla de Avila, Cameron T. Locklear, Natsu Fukui, Aimal Arsalla, Trevor Gogoll, Zobair M. Younossi Introduction: NAFLD is associated with cirrhosis and its complications. Although most patients with NAFLD are overweight and obese, some NAFLD patients are considered lean. Aim: Our aim was to compare the long-term outcome of lean patients with NAFLD to overweight/obese NAFLD patients. Methods: The National Health and Nutrition Examination Survey-III (NHANES-III) (1988-1994) was used for this study. The study cohort was followed through 31 December 2011 via linkage to the National Death Index. The Underlying Cause of Death 113 codes were used to establish causes of death. NAFLD was defined by presence of hepatic steatosis by ultrasound in the absence of other causes of liver disease. Individuals were classified according to their BMIs as lean (BMI<25), overweight (BMI 25-30) and obese (BMI>30). Data were analyzed in (1) lean and (2) obese/overweight cohorts, separately. Allcause mortality and hazard ratios with 95% confidence intervals (CI) were estimated by Cox proportional hazard models. All statistical tests were conducted in SAS version 9.3 and considered significant when two-sided p was <0.05. Results: Among 10,563 NHANES participants who qualified the criteria for the study, the prevalence of NAFLD was 22.7% (n= 2,397). Of NAFLD patients, 18% was lean and 82% was overweight/obese. The proportions of NAFLD patients with components of metabolic syndrome and cardiovascular diseases were higher in the overweight/obese NAFLD group than the lean NAFLD group. During 24 years follow up, there were 2,324 deaths (226,080 person-years). Overall mortality ratio was higher in the overweight/obese NAFLD group [26% (40,164 person-years)] than the lean NAFLD group [16% (8,964 person-years)]. The most common cause of death were (29%) cardiovascular diseases in the obese/overweight cohort while malignancy was the most common cause of death in the lean group(28%). Nevertheless, multivariate analysis revealed that in both groups, age, smoking history, presence of cardiovascular diseases and Index of NASH (ION) scores≥50 were independent predictors of overall mortality. On the other hand, presence of NAFLD by ultrasound was the independent predictor of overall mortality only in lean cohort. Conclusions: Overweight or obesity NAFLD have higher rates of mortality. On the other hand, presence of NAFLD is also associated with overall mortality only in lean subjects.
Figure
Mo1457 MULTIPLE EFFECTS OF PROSTAGLANDIN I2-IP SIGNALING IN THE LATER PHASE OF NONALCOHOLIC STEATOHEPATITIS Shima Kumei, Toshikatsu Okumura, Fumitaka Ushikubi ABSTRUCT: Nonalcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and it has become a global health issue. NAFLD is divided into two categories, benign simple steatosis and nonalcoholic steatohepatitis (NASH). In the later phase of NASH, cirrhosis and hepatocellular carcinoma often develop. Although earlier investigators found that cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoids biosynthesis, is up-regulated in the liver of NASH patients, a role of prostanoids in the development of NASH remains to be determined. Previously we showed that prostaglandin (PG) I2 signaling has suppressive effects in animal NASH model using PGI2 receptor IP knock-out (IP-KO) mice, which had earlier development of NASH with augmented steatosis, severe inflammatory cell infiltration and greater oxidative stress. In addition, an IP agonist showed a potent protective effect against hepatic inflammation by reducing the number of infiltrating F4/80-positive cells. However, the effect of PGI2-IP signaling on hepatic fibrosis and carcinogenesis has not been elucidated yet. AIM: The purpose of this study was to clarify whether PGI2-IP signaling exerts a protective action in the later phase of NASH. METHODS: A methionine- and choline-deficient diet (MCDD) or a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) was used for the evaluation of fibrosis and carcinogenesis, respectively. Beraprost (BPS), a specific IP agonist, was administrated orally to mice every day during the experimental periods. RESULTS: BPS successfully suppressed hepatic fibrosis in WT liver with the decreased hepatic mRNA expression levels of collagen Iα1 and tumor growth factor (TGF) β (Figure 1). Moreover, BPS drastically decreased the occurrence of hepatic tumors in WT mice (Figure 2). CONCLUSIONS: We clarified that PGI2-IP signaling has suppressive effects on the development of fibrosis and carcinogenesis in the later phase of NASH. We speculate that an IP agonist could be a potent therapeutic tool for NASH.
Mo1459 INDUCIBLE NITRIC OXIDE SYNTHASE IS INDEPENDENTLY ASSOCIATED WITH THE INCREASED HEPATIC STEATOSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) Elzafir Elsheikh, James M. Estep, Sean Felix, Hussain Allawi, Thomas Jeffers, Zahra Younoszai, Pegah Golabi, Kourosh Kalachi, Bashir Noor, Daisong Tan, Munkhzul Otgonsuren, Andrei Racila, Brian P. Lam, Jason Poff, Lynn Gerber, Zobair M. Younossi Background and Aim: NAFLD is a common cause of liver disease commonly associated with cardiovascular diseases (CVD). Hepatic steatosis is independently associated with CVD mortality. Inducible nitric oxide synthase (iNOS) is associated with CVD. In healthy livers, inducible nitric oxide synthase (iNOS) is not expressed. However, it is readily upregulated in the liver under pathological conditions. Little is known about the role of iNOS, a source of reactive nitrogen species, in NAFLD. Our aim was to assess the level of iNOS and NO synthase inhibitor [Asymmetric dimethylarginine (ADMA)] in patients with NAFLD. Methods: The study cohort consisted of 146 NAFLD patients. Each patient had fasting serum, clinical data and abdominal ultrasound. NAFLD was defined as radiologic fatty liver in the absence of other causes of liver disease and excessive alcohol use. Right kidney echogenicity was used for determination of liver parenchyma echogenicity. Hepatic steatosis was scored from 0 to 6 points by the study radiologist according to a standard protocol. A score of >2 was considered significant hepatic steatosis. iNOS (pg/mL) and ADMA (ng/mL) concentrations were determined in the fasting serum using by ELISA. Whole blood was used to genotype patients for a non-synonymous (S->L) single nucleotide polymorphism (SNP) of iNOS, rs2297518, by TaqMan genotyping assays. Results: iNOS levels were higher in NAFLD patients with significant hepatic steatosis as compared to patients with lower scores for hepatic steatosis (median 990 pg/mL vs median 903 pg/mL, p<0.01). NAFLD patients in >25th quartile of iNOS levels (>363 pg/ml) had the increased risk of significant hepatic steatosis [OR: 4.59 (95% CI: 1.93-10.9)]. In multivariate analysis, iNOS [OR: 6.98 (95% CI: 1.98-24.6)] and obesity (BMI >30 kg/m2) [OR: 2.80 (95% CI: 1.10-7.10)] were independently associated with increased risk for significant hepatic steatosis. Pairwise comparison showed significant enrichment of rs2297518 minor alleles in the "significant steatosis" patient population (P=0.02). Additionally, iNOS polymorphism was correlated with significant hepatic steatosis (OR 95% CI = 2.7 (1.3-5.8), P = 0.01). Interestingly, circulating iNOS
Figure 1. Hepatic mRNA expression levels of Collagen Iα1 and TGF β Values are expressed as means ± SEM.†P <0.05 vs. the corresponding WT mice fed normal diet *P <0.05 vs. the corresponding WT mice fed MCDD
AGA Abstracts
S-684