Effect of aging on norepinephrine-related proliferative response in primary cultured periportal and perivenous hepatocytes

Abstract

(NE) amplifies the mitogenic effect of EGF in a rat liver through the adrenergic receptor coupled with G protein, Gh␣. Gh␣ is also known as a transglutaminase 2 (TG2), whose cross-linking activity is implicated in hepatocyte growth. Recently, we found that NE-induced amplification of EGF-induced DNA synthesis in hepatocytes obtained from perivenous regions of liver is caused by inhibiting the downregulation of EGF receptor (EGFR) by TG2. In the present study, we investigated the effect of aging on NE-related proliferative response. Hepatocytes were obtained from the liver of 7-and 90-wk-old rats. To examine this in detail, periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) were isolated using the digitonin/collagenase perfusion technique. EGF or NE receptor binding was analyzed by Scatchard analysis. Changes in NE-induced DNA synthesis, G protein activity, and TG2 activity were measured. NE slightly potentiated [ 125 I]EGF binding to EGFR, and EGF-induced DNA synthesis in PVH but not in PPH.[ 3 H]NE binding studies indicated that PVH have a greater number of receptors than PPH, and that the number of receptors in both subpopulations increased with aging. NE-induced changes in G protein activity and TG2 activity in 90-wk-old rats were slight compared with 7-wk-old rats. These results suggest that NE results in a slight recovery effect on the age-related decline in EGF-induced DNA synthesis because of incomplete switching of the function from TG2 to Gh␣. transglutaminase; EGFA SIGNIFICANT DECREASE IN cell proliferation is a hallmark of aging in many cell lines (6,14,17,34,36). A regeneration of rat liver is widely used as a model of aged cell proliferative capacity and responsiveness (5, 17). The decline of DNA synthesis and loss of regeneration capacity are a typical phenomena associated with liver senescence. It has been shown that a faulty restoration of an aged liver is caused by a delayed cell cycle and a reduction of the number of proliferating hepatocytes (5, 49). However, the mechanism by which aging causes impairment of the responsiveness of DNA synthesis to various growth factors and cytokines is still unclear. Hepatocytes are distinguished between periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) on the basis of their metabolism and growth factor responsiveness (12, 32). In particular, EGF and hepatocyte growth factor (HGF) both facilitate hepatocyte proliferation. (15). Many studies have shown that EGF binds EGF receptors (EGFR) with two distinct affinities and subpopulations of EGFR (41). Macdonald and Pike (24) recently provided the evidence that affinities of EGF binding to EGFR were regulated by negative cooperativity in an aggregating system. Moreover, the driving force for asymmetry in human EGFR dimmers may arise from the intracellular region in EGFR (21). High-affinity EGFRs, which are correlated with Ras/MAPK and PI3K/Akt pathways (20), are more highly expressed in periportal than in PVH, resulting in DNA synthesis correlating to the EGFR expression level (15). We rep...

Insulin resistance in the liver: Deficiency or excess of insulin?

“…However, in the acini area, the hepatocytes are exposed to a spatial biochemical gradient that influences metabolism and gene expression, so cell specialization does exist to some degree, depending on locale. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Parenchymal acini of the liver are divisible into 2 circulatory zones, based on proximity to afferent vessels. 36 Periportal hepatocytes are supplied by blood rich in oxygen and nutrients, whereas the blood reaching perivenous hepatocytes (at the periphery of acini) is oxygen-poor and nutrient-depleted.…”

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“…Stimulation of α1-adrenoreceptors increases the nuclear volume of hepatocytes and the density of nucleoli due to the release of intracellular Ca 2+ and the subsequent activation of DNA polymerase. In addition, endotoxins and TNFα increase the volume of hepatocytes by activation of signaling pathways and retention of sodium and water [ 58 , 59 ].…”

The effect of chronic alcohol intoxication and constant illumination on the morphological and functional state of the liver

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