A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance

Yuriko Adkins, Iwan W. Schie, Dawn Fedor, Aurosis Reddy, Samantha Nguyen, Ping Zhou, Darshan S. Kelley, Jian Wu

Research output: Contribution to journalArticle

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Abstract

Currently available models insufficiently reflect the pathogenic alternation of nonalcoholic steatohepatitis/NASH), such as insulin resistance. The present study aimed to characterize a novel NASH model caused by feeding the diet containing conjugated linoleic acid (CLA). In this study, mice were fed a control diet or the diet containing 0.5% CLA for 8 weeks. The insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used to determine the extent of insulin resistance. Liver lipotoxicity and inflammation were assessed by endoplasmic reticulum (ER) stress, autolipophagy, recruitment of Kupffer cells and hepatic stellate cell (HSC) activation. We found that liver weight was markedly increased, and histopathological examination showed marked macrosteatosis with focal hepatocellular death through apoptosis, and mild pericellular fibrosis with Kupffer cell recruitment and HSC activation, as well as light chain IIIβ-positive cells and enhanced ER stress in mice fed the CLA-containing diet. Enhanced synthesis and reduced β-oxidation of fatty acids resulted in their accumulation and lipotoxicity in hepatocytes. A biophotonic technology revealed lipid droplet accumulation in the liver from mice fed the CLA-containing diet, and Raman spectroscopic analysis indicated that these lipid droplets predominantly contained saturated fatty acids. Elevated fasting insulin levels, abnormal ITT and HOMA-IR confirmed the marked insulin resistance in these mice. Decreased phosphorylation of the insulin-signaling molecule Akt was partially responsible for the significant insulin resistance. In conclusion, Mice fed the diet containing CLA-developed steatohepatitis with marked insulin resistance, which is similar to the characteristics observed in NASH patients. The further characterization of this model would be particularly useful for revealing the critical role of insulin resistance in NASH development in conditions such as metabolic syndrome, diabetes and obesity.

Original languageEnglish (US)
Pages (from-to)1313-1322
Number of pages10
JournalLaboratory Investigation
Volume93
Issue number12
DOIs
StatePublished - 2013

Fingerprint

Insulin Resistance
Conjugated Linoleic Acids
Diet
Insulin
Hepatic Stellate Cells
Endoplasmic Reticulum Stress
Kupffer Cells
Liver
Homeostasis
Fatty Acids
Non-alcoholic Fatty Liver Disease
Fatty Liver
Hepatocytes
Fasting
Fibrosis
Obesity
Phosphorylation
Apoptosis
Inflammation
Technology

Keywords

  • animal model
  • insulin resistance
  • lipid droplets
  • nonalcoholic steatohepatitis
  • raman micro-spectroscopy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. / Adkins, Yuriko; Schie, Iwan W.; Fedor, Dawn; Reddy, Aurosis; Nguyen, Samantha; Zhou, Ping; Kelley, Darshan S.; Wu, Jian.

In: Laboratory Investigation, Vol. 93, No. 12, 2013, p. 1313-1322.

Research output: Contribution to journalArticle

Adkins, Y, Schie, IW, Fedor, D, Reddy, A, Nguyen, S, Zhou, P, Kelley, DS & Wu, J 2013, 'A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance', Laboratory Investigation, vol. 93, no. 12, pp. 1313-1322. https://doi.org/10.1038/labinvest.2013.123
Adkins, Yuriko ; Schie, Iwan W. ; Fedor, Dawn ; Reddy, Aurosis ; Nguyen, Samantha ; Zhou, Ping ; Kelley, Darshan S. ; Wu, Jian. / A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. In: Laboratory Investigation. 2013 ; Vol. 93, No. 12. pp. 1313-1322.
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