Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy.
OBJECTIVE
The aim of this study was to assess the influence of severe steatosis with inflammation on hepatocellular recovery after 70% hepatectomy in a rat model of diet-induced steatosis.


BACKGROUND
Patients with steatosis have an increased risk of inflammatory complications after liver resection. This might be attributable to Kupffer cell-mediated inflammation in steatotic livers causing progressive injury.


METHODS
Male Wistar rats were fed a standard methionine- and choline-deficient diet for 1 or 5 weeks. A 70% partial hepatectomy (PH) was performed, after which rats were killed at 24, 48, or 72 hours. The extent of steatosis and inflammation was determined by assessment of hepatic triglycerides, cytokine content, and histopathology. Outcome parameters were: liver regeneration (MIB-5 proliferation rate, mitotic index, and regenerating liver mass), hepatocellular injury (plasma aminotransferases, lipid peroxidation, histopathology, and apoptosis), Kupffer cell-mediated proinflammatory response (TNF-alpha, IL-1beta, IL-6, IL-10 in plasma and liver) and antioxidant content (total glutathione).


RESULTS
Methionine- and choline-deficient diet induced uncomplicated steatosis after 1 week (<30% hepatocytes affected without inflammation) and severe steatosis after 5 weeks (>60% hepatocytes affected, including prominent inflammation) as confirmed by histopathology. After PH, liver regeneration was impaired at all time points in the severe steatosis group as compared with the mild and control groups (P < 0.05). Hepatocellular injury was significantly increased in the severe steatosis group at all time points (P < 0.05). Kupffer cell-mediated inflammatory responses were aggravated in the severe steatosis group along with decreased antioxidant content (P < 0.05). Necrosis was the main type of cell death in severe steatotic livers compared with mainly apoptotic cell death in mild steatotic and normal livers.


CONCLUSIONS
Steatosis with prominent inflammation impaired liver regeneration probably because of increased hepatocellular lipid peroxidation and damage in concert with Kupffer cell-mediated proinflammatory responses. These results suggest an increased risk of performing extensive liver resection in the presence of severe steatosis.
Veteläinen
Reeta
R
Department of Surgery, Surgical Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
van Vliet
Arlène K
AK
van Gulik
Thomas M
TM
D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D006498:Hepatectomy / Q000009:adverse effects*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index