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Characterizing A Rat Model to Study the Role Endo‐Immunology Plays in Diet‐Induced Non‐Alcoholic Fatty Liver Disease
Author(s) -
Hinojosa Gabriella,
Hamilton Alina,
Lora Jessica,
Short John D.,
Dearth Robert K
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.887.17
Subject(s) - fatty liver , steatohepatitis , steatosis , medicine , alcoholic liver disease , endocrinology , disease , physiology , cirrhosis , pathology
There is a rising epidemic of non‐alcoholic fatty liver disease (NAFLD) associated with the growing prevalence of obesity. NAFLD ranges from non‐progressive, steatosis, to a more aggressive disease, non‐alcoholic steatohepatitis (NASH). NASH, which is defined as an inflamed, fatty liver, contributes to liver cancer by causing chronic liver injury. A key event in the transitional progression from steatosis to NASH is the endocrine recruitment of monocytes to the liver. These infiltrating blood monocytes become polarized liver macrophages driving disease. There are currently no drugs specifically approved to treat NASH. One of the reasons is the availability of preclinical models that replicate disease pathophysiology in humans. A recent study showed that a specialized Amylin liver NASH Model (AMLN) diet (40% kcal from fat; fructose 22% by weight; cholesterol 2% by weight) caused NASH including immune cell infiltration in mice. However, the Sprague‐Dawley (SD) rat strain has been shown to be a more representative model to study human liver physiology and disease. Therefore, the objective of this study was to create a new model of diet‐induced NAFLD in the SD rat that more accurately maps the etiology of liver disease. Forty‐nine day old male Sprague Dawley rats were separated into groups and fed normal diet or AMLN diet for 4 weeks, 8 weeks, 12 weeks, or 19 weeks. AMLN diet rats showed a significant increase in weight gain and caloric intake weekly compared to controls. Histological analysis showed macrovesicular hepatic steatosis after four weeks on AMLN. Oil Red O staining confirmed an observable increase in lipid accumulation in the treated group after 4 weeks. After 19 weeks on AMLN, immunohistochemistry (IHC) revealed a significant increase in the macrophage markers CD68 and CC‐chemokine receptor 2 (CCR2) in the liver. CCR2 has been shown to be critical for the increased hepatic macrophage accumulation that accompanies NASH. We also observed notable clusters of hepatic macrophages indicative of advanced stages of NASH. Furthermore, we assessed changes in endo‐immuno markers known to be associated with liver disease progression. In conclusion, our rat model exhibited characteristics of diet‐induced liver injury that progresses from steatosis to NASH. This included the recruitment of blood borne monocytes that invaded the liver. This model may serve as a useful tool to elucidate the complex role endo‐immunology plays in the progression of diet‐induced NAFLD. Thus, allowing for a preclinical model that could be used to develop new drugs to treat NASH. Support or Funding Information GH, AH, and JL were supported by the National Institute of General Medical Sciences‐award Number 1R25GM100866 (awarded to RKD and JGP).