Abstract
Animal models of obstructive cholestasis and ischemia/reperfusion damage have revealed the functional heterogeneity of liver lobes. This study evaluates this heterogeneity in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) rat models. Twelve-week-old Obese and Lean male Zucker rats were used for NAFLD. Eight-week-old male Wistar rats fed with 8-week methionine-choline-deficient (MCD) diet and relative control diet were used for NASH. Gelatinase (MMP-2; MMP-9) activity and protein levels, tissue inhibitors of metalloproteinase (TIMPs), reactive oxygen species (ROS), and thiobarbituric acid-reactive substances (TBARS) were evaluated in the left (LL), median (ML), and right liver (RL) lobes. Serum hepatic enzymes and TNF-alpha were assessed. An increase in gelatinase activity in the NASH model occurred in RL compared with ML. TIMP-1 and TIMP-2 displayed the same trend in RL as ML and LL. Control diet RL showed higher MMP-9 activity compared with ML and LL. No significant lobar differences in MMP-2 activity were detected in the NAFLD model. MMP-9 activity was not detectable in Zucker rats. TIMP-1 was lower in LL when compared with ML while no lobar differences were detectable for TIMP-2 in either Obese or Lean Zucker rats. Control diet rats exhibited higher ROS formation in LL versus RL. Significant increases in TBARS levels were observed in LL versus ML and RL in control and MCD rats. The same trend for ROS and TBARS was found in Obese and Lean Zucker rats. An increased serum TNF-alpha occurred in MCD rats. A lobar difference was detected for MMPs, TIMPs, ROS, and TBARS in both MCD and Zucker rats. Higher MMP activation in RL and higher oxidative stress in the LL, compared with the other lobes studied, supports growing evidence for functional heterogeneity among the liver lobes occurring certainly in both NAFLD and NASH rats.
Highlights
Among emergent metabolic chronic liver diseases, nonalcoholic fatty liver disease (NAFLD) and its more advanced form, nonalcoholic steatohepatitis (NASH), are becoming a major public health problem in industrialized countries [1, 2]
We previously demonstrated that a functional lobar heterogeneity of the liver exists in ischemia/reperfusion and obstructive cholestasis animal models, indicating that different events such as modulation of the extracellular matrix (ECM) and oxidative stress occur with different intensities in the hepatic lobes [12, 13]
Gelatin zymography revealed a statistical difference between the liver lobes: MMP2 and matrix metalloproteinase (MMP)-9 activity was significantly increased in the right liver (RL) compared with the median lobe (ML) in the MCD rats (Figures 2(a) and 2(b))
Summary
Among emergent metabolic chronic liver diseases, nonalcoholic fatty liver disease (NAFLD) and its more advanced form, nonalcoholic steatohepatitis (NASH), are becoming a major public health problem in industrialized countries [1, 2]. The estimated worldwide prevalence is 4-46% for NAFLD and 3%-5% for NASH [3]. The highest prevalence of NAFLD is observed in Western countries (17% to 46%) where it is poised to become the most important cause of morbidity and mortality for chronic liver disease [2, 4]. Experimental models should reflect the etiology, disease progression, and pathology of human NAFLD. Currently available models, MCD diet, Western diet, and high-fat diet, are complementary and each of them partially reflects the real picture of human NAFLD [5]. The available experimental models can be classified into genetic and nutritional: the main genetic model is Zucker rat (fa/fa), a genetic model of metabolic syndrome with obesity, while the most commonly used nutritional
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