Non‐alcoholic steatohepatitis: Definitions and pathogenesis

Day, Chris; Saksena, Sushma

doi:10.1046/j.1440-1746.17.s3.31.x

Cited by 160 publications

(135 citation statements)

References 67 publications

(76 reference statements)

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“…Thus the phenotype of Nrf1LKO mice also incorporates features of nonalcoholic steatohepatitis (NASH) in humans. NASH is a chronic condition that encompasses varying degrees of hepatic injury, necrosis, and inflammation (24,25). NASH may progress to hepatocellular carcinoma (HCC), and it is recognized as another risk factor for liver cancer (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…However, a precise understanding of the pathogenesis of NASH is still lacking. One prevailing theory suggests a two-hit mechanism (24). The first hit is accumulation of hepatic fat, and the second hit is thought to result from several interrelated processes, including peripheral insulin resistance, oxidative stress, and inflammation (28).…”

Section: Discussionmentioning

confidence: 99%

“…Third, accumulated fat can also cause direct toxicity to cells and induce apoptosis in hepatocytes (34). These effects in turn lead to cellular death, inflammation, and induction of cytokines such as TNF-␣, thereby perpetuating the pathogenic process by causing mitochondrial damage and ROS production (24).…”

Section: Discussionmentioning

confidence: 99%

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Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Chen

Leung

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

270

265

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Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer. hepatocellular carcinoma ͉ oxidative stress ͉ knockout mouse T ranscription of many cytoprotective genes and phase-2 xenobiotic metabolizing genes is regulated through cis-active sequences known as antioxidant response elements (ARE) (1, 2). Regulation of ARE function is mediated by various basic leucine zipper (bZIP) transcription factors including members of the ''cap n collar'' (CNC)-bZIP and small-Maf family of proteins. Nrf1 and Nrf2 are CNC-bZIP proteins, and they function as obligate heterodimers by complexing with small-Maf and other bZIP proteins (3). An important role for Nrf2 in xenobiotic metabolism and oxidative stress response had been identified through knockout studies in mice (4-10). These and other studies indicate that Nrf2 is an important activator of AREs.In contrast, the function of Nrf1 is not fully understood. Mice deficient in Nrf1 function die during development (11). Analysis of nrf1 and nrf1::nrf2 mutant cells suggests that Nrf1 is also involved in the oxidative stress response (12, 13). However, the importance of Nrf1 in this function in an intact animal is not certain because early lethality precludes analysis of Nrf1-deficient animals beyond embryonic development. Chimeric mice generated with Nrf1-deficient embryonic stem cells showed widespread apoptosis in fetal livers at late gestation, demonstrating a cell autonomous role of Nrf1 in the survival of hepatocytes (14). This finding suggests that Nrf1 is required for normal function of hepatocytes. Based on these findings, we hypothesize that Nrf1 is critical to the oxidative stress response in the adult liver, and that it plays an important role in oxidative stress-induced liver disease. To bypass embryonic lethality, we used a Cre-lox system ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Chen

Leung

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

270

265

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“…Although they are often categorized as the insulin resistance syndrome or the metabolic syndrome (12), each of these individual abnormalities carries a risk of cardiovascular disease. In addition, diabetes, insulin resistance, and increased plasma fatty acids are considered to increase the risk for NAFLD (13,14), and each of these metabolic factors is also characteristic of type 2 diabetes. It has been reported that NAFLD influences severity of hepatic insulin resistance in type 2 diabetes (15).…”

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confidence: 99%

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Type 2 Diabetes in Middle-Aged Japanese Men

et al. 2007

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OBJECTIVE -To determine the association between nonalcoholic fatty liver disease and the risk for development of diabetes.RESEARCH DESIGN AND METHODS -We conducted an observational cohort study in male workers Ն40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake Ն20 g/day and those with impaired glucose tolerance by a 75-g oral glucose tolerance test. The remaining 3,189 workers were classified into fatty liver (FL) and non-FL group based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. Hazard ratio (HR) was determined in Cox proportional hazard analysis. A nested case-control study was conducted to determine the odds ratio (OR).RESULTS -The average age of participants was 48.0 years at the entry, and the average follow-up period was 4.0 years. The incidence of diabetes in the FL group was 2,073 per 100,000 person-years (65 cases), whereas 452 per 100,000 person-years (44 cases) in the non-FL group. The age-and BMI-adjusted HR of diabetes associated with FL was 5.5 (95% CI 3.6 -8.5, P Ͻ 0.001). In the nested case-control analysis, the OR adjusted for age and BMI was 4.6 (3.0 -6.9, P Ͻ 0.001).CONCLUSIONS -Nonalcoholic fatty liver disease significantly increases the risk of diabetes in middle-aged Japanese men. Diabetes Care 30:2940-2944, 2007N onalcoholic fatty liver disease (NAFLD) has become the most common disease of chronic liver damage, with increased prevalence of obesity, diabetes, and metabolic syndrome in the U.S. (1-3). The prevalence of NAFLD is increasing in Japan because of the westernization of the lifestyle, such as a high-fat and high-calorie diet and less physical activity (4). The high prevalence of fatty liver in association with type 2 diabetes has been reported (5,6).NAFLD is characterized by significant lipid deposition in hepatocytes in patients without history of excessive alcohol intake and is often associated with obesity (7), type 2 diabetes (8,9), dyslipidemia (10), and hypertension (11). Although they are often categorized as the insulin resistance syndrome or the metabolic syndrome (12), each of these individual abnormalities carries a risk of cardiovascular disease. In addition, diabetes, insulin resistance, and increased plasma fatty acids are considered to increase the risk for NAFLD (13,14), and each of these metabolic factors is also characteristic of type 2 diabetes. It has been reported that NAFLD influences severity of hepatic insulin resistance in type 2 diabetes (15). Moreover, NAFLD was correlated with hepatic insulin resistance independently of obesity and intra-abdominal adiposity among nonobese men without type 2 diabetes (16).Increased prevalence of NAFLD in relation to the development of diabetes has been reported in a cross-sectional study (17), and a close relationship between liver enzymes and diabetes has been reported in cohort studies (18 -23). However, the former does not prove a causal relationship, and the latter does not directly pay attention to NAFLD. There is...

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“…Due to rapid and drastic changes in lifestyle and eating habits in modern society, the number of patients suffering steatosis-associated chronic liver injury, socalled nonalcoholic fatty liver disease (NAFLD), a manifestation of metabolic syndrome in the liver, has been growing rapidly (Powell et al 1990;Angulo 2002;Day & Saksena 2002;Harrison et al 2003;El-Serag & Rudolph 2007;Ascha et al 2010;Blonski et al 2010;Nordenstedt et al 2010). NAFLD comprises a wide variety of disease criteria ranging from benign simple steatosis to progressive inflammation and fibrosis called nonalcoholic steatohepatitis (NASH), which is a prominent risk factor for the development of hepatocellular carcinoma (HCC) (Hytiroglou et al 2007;Park et al 2010;He & Karin 2011).…”

Section: Introductionmentioning

confidence: 99%

Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

et al. 2016

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The consumption of fructose, including the use of high-fructose corn syrup as a sweetener, has increased continuously in recent decades. Although the involvement of fructose in the development of metabolic diseases has been emphasized recently, whether fructose intake increases susceptibility to steatosis-associated hepatocellular carcinoma (HCC) is unclear. Here, we investigated this issue using mice lacking a circulating protein, apoptosis inhibitor of macrophage (AIM, encoded by cd5l). AIM does not induce carcinogenesis of hepatocytes, but provokes necrotic death specifically in AIM-bound cancer cells through complement cascade activation, thereby preventing HCC tumor development in wild-type mice. When subjected to a high-fructose diet (HFrD), AIM-deficient (AIM -/-) mice showed liver steatosis and subsequent liver inflammation as well as fibrosis, but at much milder levels compared with mice fed a high-fat diet. However, AIM -/-mice were markedly susceptible to HCC tumor development, whereas no wild-type mice developed the disease. Systemic metabolic states, including obesity and insulin resistance, were similar in both types of mice after HFrD challenge, indicating no influence of AIM on HFrD-induced metabolic changes. Our results suggest that dietary fructose increases the risk for liver carcinogenesis and that individuals with low blood AIM levels may be susceptible to HCC under chronic fructose intake.

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Non‐alcoholic steatohepatitis: Definitions and pathogenesis

Cited by 160 publications

References 67 publications

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Type 2 Diabetes in Middle-Aged Japanese Men

Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

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