Hepatic microvascular dysfunction during evolution of... : Hepatology (original) (raw)

Original Articles

Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice

McCuskey, Robert S.*,1,†; Ito, Yoshiya1; Robertson, Graham R.2; McCuskey, Margaret K.1; Perry, Michael3; Farrell, Geoffrey C.2

1Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ

2Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia

3Department of Physiology and Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia

E-mail:[email protected]

*Address reprint requests to: Department of Cell Biology and Anatomy, College of Medicine, P.O. Box 245044, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724-5044.

†fax: (520) 626-2097.

Received December 11, 2003; Accepted April 09, 2004; previously published online August 13, 2004

Abstract

In alcoholic steatohepatitis, hepatic microvascular changes have pathogenic significance for hepatocellular function, perisinusoidal fibrosis, and portal hypertension. It is unclear whether similar changes occur in other forms of steatohepatitis. We therefore examined whether hepatic microvascular dysfunction occurs in fibrosing steatohepatitis induced by feeding mice a high-fat methionine- and choline-deficient (MCD) diet. Using in vivo microscopic—as well as histological and electron microscopic—methods, together with measurements of alanine aminotransferase (ALT), lipid content, and oxidative stress, hepatic microvascular structure and function were studied in relation to inflammatory and fibrotic changes during evolution of steatohepatitis. At 3 weeks of MCD diet intake, serum ALT was elevated and hepatic steatosis was pronounced. By 5 weeks, necroinflammatory change was noteworthy, and by 8 weeks perisinusoidal fibrosis was established. Compared with mice receiving the high-fat diet supplemented with methionine and choline (controls), levels of hepatic lipid and lipoperoxides were elevated at 3 weeks and beyond. The numbers of perfused sinusoids were significantly reduced at each time point. Enlarged, fat-laden hepatocytes together with perivascular fibrosis narrowed sinusoidal lumens, making vessels tortuous and impairing sinusoidal perfusion. At 3 and 5 weeks, MCD diet caused significant increases in phagocytic activity of macrophages in centrilobular regions. By 8 weeks, macrophage activity was less striking, but the number of leukocytes adherent to the sinusoidal lining had increased 5-fold compared with controls. In conclusion, these results are consistent with a dysfunctional hepatic microvasculature. Thus, microvascular changes may contribute to progressive liver injury in metabolic and toxic forms of steatohepatitis. (Hepatology 2004;40:386-393.)