Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-κB (NF-κB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF.
Society has a moral obligation to provide adequate access to health care for all, concludes the President's Commission for te Study of Ethical Problems in Medicine and Biomedical and Behavorial Research in its report Securing Access to Health Care. Though the federal government's involvement is not necessary if private forces are able to achieve equity in health care delivery, the government bears the ultimate responsibility for ensuring that society fulfills its obligations. Meeting these objectives will require changes in the country's political and economic systems, which traditionally have not emphasized subordinating the individual good to the common good. The needs of the poor must take priority even at risk of burdening the advantaged. The commission recognizes that it is irresponsible to advocate equity without acknowledging the need to control costs. Greater equity can be attained only if changes in health care management practices are adopted and if decisions regarding resource use are based on social goals. Thus placing the needs of the poor first may mean a commitment to use less high-cost treatment. The report presents an opportunity to promote a more just health care policy. Catholic health care facilities, for example, can be made models of institutions that have met the needs of the poor, and they can become social justice advocates for government policies that benefit the poor and the disadvantaged.
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