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Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis.
Gastroenterology. 2007 Jan; 132(1):282-93.G

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+Show Affiliations

Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17241878

Citation

Ota, Tsuguhito, et al. "Insulin Resistance Accelerates a Dietary Rat Model of Nonalcoholic Steatohepatitis." Gastroenterology, vol. 132, no. 1, 2007, pp. 282-93.
Ota T, Takamura T, Kurita S, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132(1):282-93.
Ota, T., Takamura, T., Kurita, S., Matsuzawa, N., Kita, Y., Uno, M., Akahori, H., Misu, H., Sakurai, M., Zen, Y., Nakanuma, Y., & Kaneko, S. (2007). Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology, 132(1), 282-93.
Ota T, et al. Insulin Resistance Accelerates a Dietary Rat Model of Nonalcoholic Steatohepatitis. Gastroenterology. 2007;132(1):282-93. PubMed PMID: 17241878.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. AU - Ota,Tsuguhito, AU - Takamura,Toshinari, AU - Kurita,Seiichiro, AU - Matsuzawa,Naoto, AU - Kita,Yuki, AU - Uno,Masafumi, AU - Akahori,Hiroshi, AU - Misu,Hirofumi, AU - Sakurai,Masaru, AU - Zen,Yoh, AU - Nakanuma,Yasuni, AU - Kaneko,Shuichi, Y1 - 2006/10/12/ PY - 2006/06/22/received PY - 2006/09/21/accepted PY - 2007/1/24/pubmed PY - 2007/3/16/medline PY - 2007/1/24/entrez SP - 282 EP - 93 JF - Gastroenterology JO - Gastroenterology VL - 132 IS - 1 N2 - 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. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17241878/Insulin_resistance_accelerates_a_dietary_rat_model_of_nonalcoholic_steatohepatitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(06)02237-2 DB - PRIME DP - Unbound Medicine ER -