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Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.

ABSTRACT: Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice and cultured or treated with Fas ligand or acetaminophen after different culture times. Protein and mRNA expressions of Fas receptor, caspases-3/7/8, and Bak/Bax/Bid proteins were determined. FVB/N hepatocytes manifested rapid decreases of caspases-3/7 but not caspase-8 as culture time increased, which paralleled decreased susceptibility to apoptosis. Some changes were also found in Fas-receptor and Bak, Bax, and Bid proteins; caspase mRNA decreases were also noted. Caspase protein degradation was partially reversed by lysosomal protease but not proteasome or autophagy inhibitors. C57BL/6 and FVB/N hepatocytes behaved similarly in their limited susceptibility to apoptosis, whereas C3H/He hepatocytes show limited alterations in caspases, with consequent increased susceptibility to apoptosis. Similarly, C3H/He mice were more susceptible than C57BL/6 and FVB/N mice to Fas-mediated liver injury. Therefore there are significant mouse strain-dependent differences in susceptibility to apoptosis and selective loss of caspases upon short-term hepatocyte culture, with consequent decrease in susceptibility to apoptosis. These differences likely reflect genetic modifiers that provide resistance or predisposition to hepatocyte death.

SUBMITTER: Weerasinghe SV

PROVIDER: S-EPMC5063609 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.

Weerasinghe Sujith V W SV Park Min-Jung MJ Portney Daniel A DA Omary M Bishr MB

Molecular biology of the cell 20160817 20

Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice and cultured or treated with Fas ligand or acetaminophen after different culture times. Protein and mRNA expressions of Fas receptor, caspases-3/7/8, and Bak/Bax/Bid proteins were determined. FVB/N h ...[more]

PMID: 27535425

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Project description:Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis; however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought to be one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD-like interleukin-1?-converting enzyme [FLICE]) into the death-inducing signaling complex (DISC) while increasing recruitment of cellular FLICE-inhibitory protein L (FLIPL) into the DISC. Those effects may be mediated through activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway as evidenced by increased cellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3) content and PI3K activity and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIPL expression, and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.IMPORTANCE Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The antiapoptotic activity of HBSP is important for understanding hepatitis B virus pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may downregulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that Akt is centrally involved in Fas-induced hepatocyte apoptosis and revealed that interventions directed at inhibiting the activation or functional activity of Akt may be of therapeutic value in this process.

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Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.

Publications

Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.

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