Transgenic mice expressing nuclear sterol regulatory element–binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis

doi:10.1016/j.metabol.2006.11.004

Metabolism

Volume 56, Issue 4, April 2007, Pages 470-475

https://doi.org/10.1016/j.metabol.2006.11.004 Get rights and content

Abstract

Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases associated with insulin resistance. Here we report that nuclear sterol regulatory element–binding protein 1c (nSREBP-1c) transgenic mice, an inherited lipodystrophic model with severe insulin resistance, spontaneously develop steatohepatitis. The animal had marked fatty liver accompanied by hyperglycemia, hypoleptinemia, and hypoadiponectinemia. Liver histology similar to NASH, that is, mononuclear cell infiltration, pericellular fibrosis, ballooning degeneration, and Mallory hyaline body formation were seen in the livers from transgenic mice 20 weeks or older. In contrast, no liver histologic abnormalities were noted in wild-type mice aged 30 weeks. Immunoreactive 8-hydroxy-2′-deoxyguanosine was observed in the nuclei of livers from transgenic mice, suggesting that in addition to insulin resistance, oxidative stress may be involved in the development of the NASH-like lesion. Thus, the nSREBP-1c transgenic mouse may serve as a unique model of spontaneously occurring NASH.

Introduction

Nonalcoholic hepatic steatosis in obese subjects had been considered a benign condition. However, it can progress to nonalcoholic steatohepatitis (NASH), which is histologically characterized by macrovesicular steatosis, hepatocellular ballooning, and mild intralobular inflammation with scattered polymorphonuclear leukocytes and monocytes [1], [2], [3], [4]. Furthermore, NASH may deteriorate to either liver cirrhosis or hepatocellular carcinoma. Although the molecular mechanism for the transformation from steatosis to NASH is still unclear, it is obvious that insulin resistance plays a key role in the pathogenesis of NASH [5], [6], [7]. Main features of the metabolic syndrome such as obesity, diabetes mellitus, insulin resistance, and hyperlipidemia have been reported as risk factors of NASH [7], [8], [9]. Furthermore, increased oxidative stress has been implicated in the development of NASH as a second hit [10].

Generalized lipodystrophy is characterized by diminished adipose tissue and ectopic triglyceride accumulation. Despite the marked difference in fat distribution, obesity and lipodystrophy share common metabolic disorders including insulin resistance and liver steatosis, potentially leading to NASH [11], [12], [13], [14]. Some recent studies have shown that liver biopsy specimens from lipodystrophic patients frequently meet histologic criteria for NASH [15], [16].

Sterol regulatory element–binding protein 1c (SREBP-1c) is a transcription factor that is involved in adipocyte differentiation [17], [18]. Transgenic mice overexpressing nuclear SREBP-1c (nSREBP-1c) in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter developed lipodystrophy accompanied by insulin resistance and hyperglycemia [19]. The transgenic mice had severe fatty liver from birth, although the natural course of liver pathology has not been reported. In this study we histologically examined the liver from nSREBP-1c transgenic mice up to 50 weeks of age and found that most animals developed inflammatory changes together with pericellular fibrosis characteristic to NASH.

Section snippets

Animals

The experimental protocol has been approved by the Ethics Review Committee for Animal Experimentation of Kurume University School of Medicine, Fukuoka, Japan. Transgenic mice (C57BL/6 background) expressing nSREBP-1c in adipose tissue [19] were purchased from The Jackson Laboratory (Bar Harbor, ME). They were bred in our laboratory, mating to wild-type C57BL/6 mice (Jackson), in plastic cages with wood chip bedding at a temperature of 18°C to 22°C, moisture of 40% to 60%, and on a 12-hour

Results

To confirm the metabolic characteristics of lipodystrophic nSREBP-1c transgenic mice used in this study, we performed a glucose tolerance test at the age of 20 weeks (Fig. 1A). The transgenic mice had higher plasma glucose levels than wild-type mice before and 120 minutes after glucose loading. Intraperitoneal insulin tolerance tests (0.25 U/kg weight) performed at 15 weeks of age showed that the reduction rate of plasma glucose was significantly lower in transgenic mice than in wild-type mice

Discussion

In this study we found that lipodystrophic mice expressing nSREBP-1c in the adipose tissue developed NASH-like lesions in the liver. The transgenic mice showed insulin resistance and hyperglycemia accompanied by hyperlipidemia and marked fatty liver. Examination of HE-stained sections demonstrated macrovesicular steatosis in transgenic mice humanely killed at the age of 10, 20, 30, or 50 weeks. Most of the 30-week-old mice exhibited intralobular inflammation with ballooning degeneration and

Acknowledgment

This study was supported by Grant-in-Aid for Scientific Research (B) 17790619 from the Japan Society for the Promotion of Science.

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Transgenic mice expressing nuclear sterol regulatory element–binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Acknowledgment

Am J Gastroenterol

Gastroenterology

Am J Gastroenterol

Hepatology

Hepatology

J Hepatol

Gastroenterology

J Pediatr

Cell

Cell

Am J Geriatr Psychiatry

Gastroenterology

J Hepatol

Hepatol Res

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease

Mayo Clin Proc