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    Abstract:
    We examined the effect of dietary conjugated linoleic acid (CLA) on liver regeneration after a partial hepatectomy (PH) in Sprague-Dawley rats. PH was performed on rats fed a 0 or 1 wt.% CLA diet for 3 wk. Average liver weight in the CLA fed rat population was heavier than the control rat population at the time of PH and 1-d after PH. Conversely. CLA fed rats' liver weight was significantly lower than control rats at 7-d after PH. This suggests that dietary CLA reduced liver weight gain after PH. Dietary CLA did not affect serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activities. However. CLA significantly reduced serum albumin levels at 1-d but not at 7-d after PH. 5-Bromo- and 5-iododeoxyuridine incorporation into hepatocytes 1-d post PH was lower in the CLA group. In conclusion, the data suggests that dietary CLA inhibits DNA synthesis after PH, which results in hepatocyte proliferation inhibition.
    Keywords:
    Liver Regeneration
    To determine the role of TNF-driven inflammation in self-regulation of cell growth and differentiation, mouse liver regeneration after partial hepatectomy was examined for TNF-driven inflammation. Hepatectomy provoked priming state for TNF production in both whole body and liver on day 3 when the peak mitotic response occurred. Histochemical studies of liver also showed an inflammatory symptom; hepatocellular necrotic foci appeared by 6 hours after hepatectomy. TNF itself was secreted spontaneously in liver transiently on day 1 to 2 after hepatectomy just before the proliferation of hepatocytes. Dexamethasone reduced both TNF secretion and hepatocyte proliferation after hepatectomy. Recombinant murine TNF stimulated the in vitro proliferation of hepatocytes. These findings indicate that hepatectomy induces short-term secretion of TNF in liver and TNF-driven inflammation has an important role in liver regeneration, at least in part by the direct stimulation of hepatocyte proliferation.
    Liver Regeneration
    Citations (24)
    This study examines the effect of experimental diabetes on the release of rat insulin-like growth factor I (rlGFI) and its binding protein (IGF-BP) by adult rat hepatocytes in primary culture. Rats treated with streptozotocin (75 mg/kg) had decreased serum rIGF-I values of 0.37 ± 0.04 U/ml compared to 1.06 ± 0.04 in age-matched untreated rats (1 U = 770 ng human IGF-I). Concomitant decreases in hepatocyte production rates for rIGF-I (15% of the rate in cells from normal rats) and IGF-BP (30% of normal) were also observed for hepatocytes isolated from diabetic rats. Insulin replacement therapy (1.2 U/ day) for 3–4 days normalized serum rIGF-I levels (0.92 ± 0.07 U/ml) and increased rIGF-I production by isolated hepatocytes to 67% the rate of normal cells and IGF-BP production to 70% normal. Treatment of streptozotocin-treated rats with rGH (150 μg/day) in vivo for 7 days failed to increase serum rIGF-I levels or hepatocyte production of rIGF-I. Insulin in vitro (3 × 10–7m) increased rIGF-I release by hepatocytes from nondiabetic rats, but had no effect on cells from diabetic animals, suggesting that factors other than insulin are required to maintain rIGF-I synthesis in diabetes. Serum rIGF-I levels showed a strong correlation with hepatocyte rIGF-I production in the animals used in this study. However, calculation of circulating rIGF-I half-life based on these values showed a 2-fold higher half-life in diabetic rats (7.91 ± 1.58 h) and rGH-treated diabetic rats (7.52 ± 1.25 h) than in nondiabetic (2.99 ± 0.35 h) and insulin-treated diabetic animals (3.85 ± 0.36 h). This suggests that the rate of clearance of circulating rIGF-I may be slower in diabetic animals. (Endocrinology119: 2346–2352, 1986)
    Citations (77)
    The cellular mechanisms by which carbohydrate refeeding reverses the effect of fasting on T3 metabolism were studied in primary cultures of hepatocytes (24 h) harvested from 48-h fasted rats. Net T3 neogenesis (T3 generated from T4) in the fasted hepatocyte preparations (9.2 ± 0.9 pmol/min · 100 mg protein) was significantly less (P < 0.001) than that in hepatocyte cultures derived from 72-h glucose-fed rats (41 ± 0.8 pmol/ min-100 mg protein). Preincubation (18 h) with either glucose (2.5-10 mM) or insulin (10-500 nM) significantly increased the fasted hepatocyte T3 levels to 28 ± 0.6 and 22 ± 1.3 pmol/min- 100 mg protein, respectively. Furthermore, incubation with both of these agents demonstrated a greater effect on hepatic T3 neogenesis than with either alone. Fasted hepatocyte T3 neogenesis was enhanced by enrichment with dithiothreitol (5 mM), but the T3 generation remained significantly less than that in cells exposed to glucose or insulin. Studies with glucose analogs demonstrated that preincubation with 2-deoxyglucose (5 mM) significantly increased (P < 0.001) hepatocyte T3 neogenesis, but 3-O-methylglucose (5 mM) had no effect. In contrast, the insulin-mimetic compounds Concanavalin- A or spermine did not stimulate T3 neogenesis in the fasted hepatocyte cultures. Thus, rat hepatocytes sustained in primary culture for 24 h retain the T3 metabolic characteristics of the intact animal. Glucose and insulin reverse the effect of fasting on hepatocyte T3 neogenesis. The additive response to glucose and insulin suggests that T3 neogenesis is modulated through different mechanisms. The replication of the glucose effect by 2-deoxyglucose and the inability of dithiothreitol to reverse the effect of fasting on hepatocyte T4 5′-deiodinase activity suggest that neither intermediates in the glycolytic pathway nor thiol cofactors mediate the glucose effect. Thus, the restoration of liver T3 metabolism consequent to carbohydrate refeeding of the fasted rat may be mediated by the glucose and insulin responses. (Endocrinology121: 858–864,1987)
    Neogenesis
    Carbohydrate Metabolism
    Citations (23)
    Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rβ and IL-22Rα. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Rα mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-α. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-α cascades.
    Liver Regeneration
    Citations (106)
    We recently demonstrated that adipocyte deficiency of angiotensinogen (AGT) ablated high-fat diet–induced elevations in plasma angiotensin II (Ang II) concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic AGT. Therefore, in this study, we defined the contribution of hepatocyte-derived AGT to obesity-induced elevations in plasma AGT concentrations and hypertension. Male Agt fl/fl mice expressing albumin-driven Cre recombinase were bred to female Agt fl/fl mice to generate Agt fl/fl or hepatocyte AGT–deficient male mice ( Agt Alb ). Mice were fed a low-fat or high-fat diet for 16 weeks. Hepatocyte AGT deficiency had no significant effect on body weight. Plasma AGT concentrations were increased in obese Agt fl/fl mice. Hepatocyte AGT deficiency markedly reduced plasma AGT and Ang II concentrations in lean and obese mice. Moreover, hepatocyte AGT deficiency reduced the content and release of AGT from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mm Hg) and obese Agt Alb mice (by 54 mm Hg) compared with Agt fl/fl controls. To define mechanisms, we quantified effects of Ang II on mRNA abundance of megalin, an AGT uptake transporter, in 3T3-L1 adipocytes. Ang II stimulated adipocyte megalin mRNA abundance and decreased media AGT concentrations. These results demonstrate that hepatocytes are the predominant source of systemic AGT in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte AGT–deficient mice may have limited megalin-dependent uptake of AGT into adipocytes for the production of Ang II in the development of obesity-hypertension.
    Hepatocyte and soleus muscle insulin binding and the rate of insulin stimulated glycogen synthesis were examined in normal lean and genetically obese diabetic (ob/ob) mice with age. In ob/ob mice a significant decrease in the concentration of high affinity hepatocyte insulin receptors and insulin binding to soleus muscle at 10-20 and 10-40 weeks of age respectively was associated with an age related development of insulin resistance characterized by increased body weight, plasma insulin and plasma glucose. In lean mice a significant reduction in the concentration of low affinity hepatocyte receptors and soleus muscle insulin binding was observed at 60 weeks and associated with a marginally increased plasma insulin concentration and unchanged level of glycaemia. Insulin stimulated glycogen synthesis was unchanged with age in lean mouse soleus muscle but in ob/ob was significantly reduced by 5 weeks and preceded the reduction in insulin binding in this tissue. In 40 week ob/ob mice insulin sensitivity was improved and characterized by a reduction in body weight, plasma insulin and glucose, increased hepatocyte high affinity insulin receptor concentration and decreased affinity, Ke. Although insulin binding to soleus muscle was not increased and there was no improvement in insulin stimulated glycogen synthesis at this age, the increased hepatocyte insulin binding was probably not the primary cause of the improved insulin sensitivity which was most likely mediated at post-receptor loci.
    Citations (14)