Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice

Larter, Claire Z.; Yeh, Matthew M.; Rooyen, Derrick M. Van; Teoh, Narci C.; Brooling, John; Hou, Jing; Williams, Jacqueline; Clyne, Matthew; Nolan, Christopher; Farrell, Geoffrey C.

doi:10.1111/j.1440-1746.2009.05996.x

Cited by 78 publications

(102 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As reported [19,22], foz/foz mice were heavier than Wt at 3 and 6 mths ( Figure 1A), with increased adiposity (peri-epi-didymal white adipose tissue (WAT) mass; Figure 1B) and hepatomegaly ( Figure 1C Figure 2A). As shown in Figure 2B, histological examination of these tumors showed features described as the steatohepatitic variant of HCC, with large-droplet steatosis and mild inflammatory cell infiltration [23].…”

Section: Den-induced Hepatocarcinogenesis Is Accelerated In Foz/ Foz supporting

confidence: 71%

See 1 more Smart Citation

Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kB or Akt/mTORC1

et al. 2016

View full text Add to dashboard Cite

Background: There are strong links between obesity, diabetes and hepatocellular carcinoma (HCC), but molecular mechanisms remain unclear. Aim: We tested the proposed involvement of NF-κB, IL-6/STAT3 and Akt/mTORC1 before onset (at 3 months) and at onset (6 months) of accelerated hepatocarcinogenesis in DEN-injected obese and diabetic foz/foz compared to lean wildtype (Wt) mice, and also studied the hepatocyte proliferative response to DNA damage between the obese and lean lines. Methods:Male foz/foz and Wt littermates fed normal chow were DEN-injected (10mg/kg i.p.) at age 12-15 days. To test the effect of mTOR inhibitor on growth of dysplastic hepatocytes, a separate cohort of DEN-injected foz/foz mice was administered rapamycin (4 mg/kg body weight/day). Results: foz/foz mice developed obesity, hyperinsulinemia, diabetes, adipokine dysregulation and fatty liver, without increased serum or liver TNF-α or serum IL-6. All DEN-injected foz/foz mice developed HCC by 6 mths vs. 0/10 lean Wt. At 3 mths, there were more dysplastic hepatocytes in DEN-injected foz/foz than Wt, with increased liver injury (serum ALT), hepatocyte apoptosis (M30-positive cells) and proliferation (cyclin D1, cyclin E, PCNA), but neither NF-κB nor STAT3 activation. foz/foz livers exhibited upregulation of DNA damage sensors ATM and ATR, with inadequate cell cycle checkpoint controls (CHK1, CHK2, p53, p21). Akt and mTORC1 were highly activated in livers from foz/foz vs. Wt mice. Despite such activation, rapamycin failed to reduce growth of dysplastic hepatocytes. Conclusions: Accelerated DEN-induced HCC in obese/diabetic mice is linked to enhanced growth of dysplastic hepatocytes that cannot be attributed to NF-κB or IL-6/STAT3 activation, nor to sustained mTORC1 activation. The critical mechanism for obesity-enhanced hepatocarcinogenesis lies in the disconnection between hepatocellular injury with DNA damage, and an unrestrained proliferative response. Relevance for patients: This study supports the epidemiological data linking obesity, diabetes and fatty liver disease with increased risk for developing HCC. The findings also suggest that mTORC1 inhibition may not be beneficial in the prevention of obesity-related hepatocarcinogenesis.

show abstract

Section: Den-induced Hepatocarcinogenesis Is Accelerated In Foz/ Foz supporting

confidence: 71%

“…Gene and protein expression were assayed using semi-quantitative real time PCR and immunoblotting, respectively as previously reported [22]. Primer sequences and antibody conditions will be supplied upon request.…”

Section: Analysis Of Hepatic Genes and Proteinsmentioning

confidence: 99%

Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kB or Akt/mTORC1

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Therefore, the increased fat intake could be a contributing factor for central adiposity and hepatic steatosis. It has also been shown that a high-fat diet in genetically predisposed obese and diabetic mice caused earlier onset of steatohepatitis and rapid transformation of simple steatosis to fibrosing steatohepatitis (Larter et al, 2009). This observation suggests that diet therapy, particularly control of fat content in meals, should be recommended in NAFLD subjects.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that patients with NAFLD consuming a diet high in carbohydrates have greater odds of hepatic inflammation (Kang et al, 2006) suggesting a link between diet and liver injury. It has also been reported that there is an early development of steatohepatitis in obese, hypercholesterolemic, diabetic foz/foz mice fed on high-fat diet for 12 months (Larter et al, 2009). However, the inter-relations of NAFLD, MS, dietary composition and physical activity have been sparsely studied in asymptomatic healthy individuals.…”

Section: Introductionmentioning

confidence: 99%

A case-control study on nutritional risk factors in non-alcoholic fatty liver disease in Indian population

et al. 2011

View full text Add to dashboard Cite

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is considered an integral part of metabolic syndrome (MS). We aimed to explore the inter-relations of MS and dietary composition in subjects with and without hepatic steatosis and to identify the nutritional risk factors contributing to NAFLD. Subjects/Methods: In all 98 subjects with steatosis and 102 controls were selected for the study after screening 260 consecutive healthy individuals. Anthropometric and nutritional information, biochemical data and clinical profile were analyzed. Prevalence of MS was determined based on the consensus statement for diagnosis of MS for Asian Indians. Multiple logistic regression analysis was done to predict the dietary risk factors in NAFLD. Results: Prevalence of MS was 44.9% among NAFLD cases and 25.5% among controls (P ¼ 0.003). Subjects with NAFLD had significantly higher values of body mass index (BMI), waist circumference (WC), percent body fat, total cholesterol, triglycerides and blood pressure than controls. The total calorie intake, percent of carbohydrate and fat intake of NAFLD cases was significantly higher than controls. Multiple logistic regression analysis showed BMI (odds ratio 6.03 (95% confidence interval 3.26-11.14)), WC (5.49 (2.59-11.57)) and percent dietary fat intake (2.51 (1.99-3.31)) as independent nutritional risk factors in NAFLD. Conclusions: In this study, there is a high prevalence of MS among subjects with steatosis and metabolic disorders were closely related to NAFLD. BMI, WC and percent fat intake are independent dietary risk factors in NAFLD. Decreased nutritional intake with restricted fat may constitute an important therapy in subjects with NAFLD.

show abstract

“…3 Dietary deficiency of methionine and choline also contribute to development of steatosis and mild fibrosis, without obesity and insulin resistance. 3 In this regard, Larter et al 32 recently reported that foz/foz mice, carrying truncating mutation in Alms1, demonstrated both obesity and NASH-like liver histologic features during long-term feeding of an HFD. This study has established MC4R-KO mice fed the HFD for a relatively short time as a novel rodent model of NASH with obesity, insulin resistance, and excessive accumulation of lipids and enhanced fibrosis in the liver.…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Ichii

Suganami

Nakagawa

et al. 2011

The American Journal of Pathology

146

149

View full text Add to dashboard Cite

Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor-deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating Nonalcoholic fatty liver disease (NAFLD) is characterized by increased accumulation of lipids in the liver without a history of excessive alcohol consumption or known liver disease.1 NAFLD often occurs with the metabolic syndrome, a constellation of visceral fat obesity, impaired glucose metabolism, atherogenic dyslipidemia, and elevated blood pressure, and is considered the hepatic manifestation of the metabolic syndrome.2 Patients with nonalcoholic steatohepatitis (NASH), a subset of NAFLD, are at high risk for progression to cirrhosis and hepatocellular carcinoma (HCC). However, the molecular mechanisms involved in disease progression from simple steatosis to NASH to HCC are currently unclear. This is in part because there are no appropriate animal models that reflect a liver condition of human NASH, although many attempts have been made to generate animal NASH models via genetic, dietary, and pharmacologic approaches. 3The pathogenesis of NASH is thought to involve a multistep process in which the first step is excessive accumulation of lipids in the liver. According to the "two hit" hypothesis, the development of NASH requires the presence of additional pathogenic factors such as oxidative stress, endotoxins, cytokines, chemokines, and lipotoxicity. 4 -6 Because NASH is often associated with visceral fat obesity, there should be a mechanistic link

show abstract

Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice

Cited by 78 publications

References 33 publications

Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kB or Akt/mTORC1

Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-kB or Akt/mTORC1

A case-control study on nutritional risk factors in non-alcoholic fatty liver disease in Indian population

Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis

Contact Info

Product

Resources

About