Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNF␣/ ActD)-induced apoptosis. Conclusion: Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction. (HEPATOLOGY 2008;48:1942-1953

No abstract

[3H]glutamate, [3H]alpha-ketoglutarate or [3H]aspartate was injected in physiological concentrations into antegrade (from portal to hepatic vein) or retrograde (from hepatic to portal vein) perfused rat liver, and the tissue distribution of radioactivity was studied by histoautoradiography. Independent of the direction of perfusion, radioactivity was accumulated in a small perivenous liver parenchymal cell population, which surrounded the terminal hepatic venules as a layer of about two to five cells thick. In contrast, accumulation of radioactivity in periportal hepatocytes was low and sometimes not detectable. This distribution pattern roughly resembled that described for the immunohistochemical distribution of glutamine synthetase in liver. The present histoautoradiographic findings demonstrate a predominant uptake of vascular glutamate, aspartate and ketoglutarate into a small perivenous cell population. They confirm previous label incorporation studies in the metabolically intact liver, demonstrating an almost exclusive uptake of vascular glutamate and alpha-ketoglutarate into perivenous glutamine synthetase containing hepatocytes. In addition, evidence is presented suggesting that perivenous uptake of alpha-ketoglutarate may be one determinant for hepatic glutamine synthesis, at least under the experimental conditions used here.