We thank Drs. Feng and Xu for their interest in our recent article published in HEPATOLOGY. The authors bring up a very interesting point regarding the similarities in impairment of liver regeneration between steatosis and concanavalin A–induced hepatitis. Our laboratory has a strong interest both in the mechanisms of liver regeneration but also in the development and progression of fatty liver disease.1, 2 Although we did not directly observe increases in lipid accumulation by routine histopathological examination, we did not perform a systematic evaluation of this possibility in our study as Drs. Feng and Xu have done. In our recent report, we speculated that disruption in key proproliferative cytokine production (particularly interleukin-6) in conjunction with increased expression or activation of inhibitory factors such as p21 and Smad2 likely contribute to the decreased hepatocellular proliferation observed following partial hepatectomy in concanavalin A–pretreated mice, though we stopped short of defining a direct connection. This point should be clarified, because we do not believe that oval cells reduce hepatocellular proliferation but that decreased mature hepatocyte proliferation stimulates or promotes the expansion of oval cells secondarily within the regenerating liver. The inclusion of lipid accumulation as the intermediary between T cell–mediated hepatitis and inhibition of hepatocellular regeneration is novel and most interesting.
There is copious evidence in the literature to suggest a connection between lipid accumulation within hepatocytes and their decreased propensity or ability for proliferation.3 Likewise, there is evidence to suggest that key proinflammatory cytokines including tumor necrosis factor α and others may modulate the development and progression of hepatosteatosis.4–6 The ability of T cells to either directly or indirectly modify lipid accumulation within hepatocytes has not been investigated, though very recent preliminary studies by our laboratory would suggest that T cells themselves may indeed contribute to the progression of hepatosteatosis.
Together, the findings by Drs. Feng and Xu and our recent preliminary data provide an important and exciting connection between concanavalin A–induced, T cell–mediated liver injury and hepatocellular lipid accumulation. Future investigation into the direct mechanisms by which this occurs will provide the experimental and clinical community with important information regarding the impact of lymphocyte-mediated liver injury on the initiation or enhancement of secondary pathologies including hepatosteatosis.