Animal Models of Steatosis (NAFLD) and Steatohepatitis (NASH) Exhibit Hepatic Lobe-Specific Gelatinases Activity and Oxidative Stress

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.

Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

“…We found hepatic TBARS concentration to be significantly higher in the CDAHFD groups than in the ND groups. This is consistent with an increase in the liver reactive oxygen species and TBARS concentrations in other studies on NASH models (6,7,23,24). In contrast, we could partly observe the expected increase the levels of TBARS in the mice with renalase KO.…”

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

“…In relation to TIMPs dysregulation in obese adipose tissue, it has been observed an increase of TIMP-1 and -2 in patients with metabolic syndrome and diabetes [53]. In fact, these two enzymes may be considered as markers of non-alcoholic fatty liver disease (NAFLD) [69,70,71]. On the one hand, the authors reported an increase TIMP-1 levels in the serum of patients with gestational diabetes mellitus [72] and patients with obesity and cardiovascular risk [63].…”

Curcuma longaandTrigonella foenum graecum‐enriched nutrient mixture from germinatedMacrotyloma uniflorumandVigna radiateameliorate nonalcoholic fatty liver diseases in rats

“…The MMPs are zinc‐dependent endopeptidases that participate in the extracellular matrix (ECM) remodeling. The activity of MMP‐2 and MMP‐9 has been noted to increase in the early‐stage liver disease itself and the inflammatory period of NASH (D’Amico et al, ; Palladini et al, ). In the present study, nutrient mixture supplementation has reduced MMP‐9 in NASH animals and these findings are consisting of reduced Sirius red positivity for fibrosis.…”