Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis.

Abstract

BACKGROUND & AIMS:

The increasing prevalence of nonalcoholic steatohepatitis (NASH) is due to the epidemic of obesity and type 2 diabetes, both of which are associated with insulin resistance.

METHODS:

To clarify the causal relationship between insulin resistance and the development of NASH, steatohepatitis was induced in obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats by feeding them a methionine and choline-deficient (MCD) diet. Insulin sensitivity of the rats was altered by adding a high-fat (HF) diet or the peroxisomal-proliferator activated receptor-gamma agonist pioglitazone to the MCD diet.

RESULTS:

The MCD diet-induced steatohepatitis was accelerated in OLETF rats after 8 weeks. Steatosis preceded inflammation, which led to fibrosis and the development of steatohepatitis. The hepatic gene expression for transforming growth factor-beta, alpha1 procollagen and plasminogen activator inhibitor-1 was up-regulated in OLETF rats compared with LETO rats. The MCD + HF diet further enhanced insulin resistance and led to rapid development of pre-cirrhosis in OLETF rats by increasing the triglyceride pool, activating stellate cells, and up-regulating gene expression for sterol regulatory element-binding protein-1c and fatty acid synthase in the liver. In contrast, pioglitazone attenuated the MCD diet-induced steatohepatitis in OLETF rats but not in LETO rats by reversing the underlying pathogenesis involved in this model through improvement of insulin resistance. These results confirm a link between insulin resistance and the development/progression of steatohepatitis, at least partly via up-regulation of genes for lipogenesis, inflammation, and fibrogenesis, in animal models.

CONCLUSIONS:

Insulin resistance and/or diabetes may accelerate the entire pathologic spectrum of NASH.

• Authors: Tsuguhito Ota, Toshinari Takamura, Seiichiro Kurita, Naoto Matsuzawa, Yuki Kita, Masafumi Uno, Hiroshi Akahori, Hirofumi Misu, Masaru Sakurai, Yoh Zen, Yasuni Nakanuma, Shuichi Kaneko
• Journal: Gastroenterology (Gastroenterology) Vol. 132 Issue 1 Pg. 282-93 (Jan 2007) ISSN: 0016-5085 [Print] United States
• PMID: 17241878 (Publication Type: Journal Article)

Chemical References

• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Dietary Fats
• Hypoglycemic Agents
• PPAR gamma
• Plasminogen Activator Inhibitor 1
• RNA, Messenger
• Sterol Regulatory Element Binding Protein 1
• Thiazolidinediones
• Transforming Growth Factor beta
• Methionine
• Choline
• Pioglitazone

Topics

• Animal Feed
• Animals
• Choline (pharmacology)
• Collagen Type I (genetics)
• Collagen Type I, alpha 1 Chain
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, physiopathology)
• Dietary Fats (pharmacology)
• Disease Models, Animal
• Fatty Liver (metabolism, pathology, physiopathology)
• Hyperinsulinism (drug therapy, metabolism, physiopathology)
• Hypoglycemic Agents (pharmacology)
• Insulin Resistance (physiology)
• Liver (drug effects, pathology)
• Male
• Methionine (deficiency, pharmacology)
• Obesity (drug therapy, metabolism, physiopathology)
• PPAR gamma (agonists)
• Pioglitazone
• Plasminogen Activator Inhibitor 1 (genetics)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred OLETF
• Rats, Long-Evans
• Sterol Regulatory Element Binding Protein 1 (genetics)
• Thiazolidinediones (pharmacology)
• Transforming Growth Factor beta (genetics)
• Up-Regulation (physiology)