Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity

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Endogenous Benzodiazepine Receptor Ligands in Human and Animal Hepatic Encephalopathy

The role of endogenous benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy was studied in humans and in rat models of hepatic encephalopathy. Endogenous benzodiazepine ligands were extracted from rat brain and human CSF by acid treatment and purification by HPLC. Detection and partial characterization of these endogenous benzodiazepine ligands were carried out using both radioreceptor binding assays and radioimmunoassays with anti-benzodiazepine antibodies. Four different benzodiazepine receptor ligands were identified in human and rat tissue, two of which may be diazepam and desmethyldiazepam, based on elution profiles and anti-benzo-diazepine antibody reactivity. Human CSF and serum from patients with hepatic encephalopathy contained approximately 10 times more endogenous benzodiazepine receptor ligand than CSF from controls or nonencephalopathic patients with liver disease. The levels of brain benzodiazepine receptor ligand compounds were also increased approximately 10-fold in rats suffering from fulminant hepatic failure, but not in rats with portacaval shunts, a model of chronic hepatic disease. The increased concentrations of these substances could be behaviorally significant and may contribute to the pathogenesis of hepatic encephalopathy.     

GABAA Receptor Complex in an Experimental Model of Hepatic Encephalopathy: Evidence for Elevated Levels of an Endogenous Benzodiazepine Receptor Ligand

The involvement of the gamma-aminobutyric acidA (GABAA) receptor complex in the pathogenesis of hepatic encephalopathy was examined in thioacetamide-treated rats with fulminant hepatic failure. Partially purified extracts from encephalopathic rat brain were approximately three times more potent in inhibiting [3H]Ro 15-1788 binding to benzodiazepine receptors than identically prepared extracts from control rats. High levels of inhibitory activity were also found in extracts of plasma, heart, and liver from thioacetamide-treated rats. The inhibition of [3H]Ro 15-1788 binding by brain extracts appeared to be competitive and reversible and was unaffected by treatment with either proteolytic enzymes or boiling. Further, GABA significantly enhanced the potency of these extracts in inhibiting [3H]flunitrazepam binding. In contrast, no differences were found in radioligand binding to the constituent recognition sites of the GABAA receptor complex in well-washed brain membranes prepared from control and encephalopathic animals. These findings suggest that the recognition-site qualities of the constituent proteins of the GABAA receptor complex are unchanged in an experimental model of hepatic encephalopathy. However, significant elevations in the level of a substance or substances with neurochemical properties characteristic of a benzodiazepine receptor agonist may contribute to the electrophysiological and behavioral manifestations of hepatic encephalopathy.     

脐血浆治疗大鼠实验性肝衰竭及其机制的研究

本文采用脐血浆治疗实验性肝衰竭大鼠模型,并与成人血浆的疗效进行了比较。结果表明,脐血浆降低大鼠死亡率、血谷丙转氨酶水平,总胆红素浓度及使甲胎蛋白水平升高均明显高于成人血浆的作用（Ｐ＜０．０５）．肝脏病理组织学也显示脐血浆具有减轻病理损害和较快修复坏死组织的作用。提示脐血浆中含有促进肝细胞再生的因子,具有显著提高实验性大鼠肝衰竭的存活率。     

Changes in DNA strand breaks in non parenchymal cells following hepatocyte regeneration in CCl4-induced rat liver injury

DNA strand breaks (nicks) in non-parenchymal cells (NPCs) in CCl₄-induced acute or chronic liver injury in rats were detected using an in situ nick translation method; their dynamic changes were analysed in relation to the proliferation pattern of hepatocytes and NPCs, as revealed by bromodeoxyuridine (BrdU)-up-take. In acute injury, hepatocyte proliferation started before centrilobular necrosis had occurred, whereas BrdU-labeled sinusoidal NPCs markedly increased only after centrilobular necrosis was apparent. DNA breakages in NPCs paralleled the proliferation pattern of these cells, suggesting that nicks are physiological, and reflect proliferation and activated gene expression. In chronic injury, liver cirrhosis developed after 9 weeks, but BrdU-labeling of hepatocytes was almost the same level as that in untreated liver. The number of BrdU-labeled NPCs showed only a slight increase, while those with DNA breakages were much more frequent in the cirrhotic stage, suggesting a significant role for NPCs in the fibrotic process. These results indicate that DNA strand breaks in NPCs act as a marker for activation states such as proliferation, differentiation and/or activated gene expression.     

TBC1D25 alleviates nonalcoholic steatohepatitis by inhibiting abnormal lipid accumulation and inflammation

Nonalcoholic fatty liver disease (NAFLD) is a strong stimulant of cardiovascular diseases, affecting one-quarter of the world's population. TBC1 domain family member 25 (TBC1D25) regulates the development of myocardial hypertrophy and cerebral ischemia–reperfusion injury; however, its effect on NAFLD/nonalcoholic steatohepatitis (NASH) has not been reported. In this study, we demonstrated that TBC1D25 expression is upregulated in NASH. TBC1D25 deficiency aggravated hepatic steatosis, inflammation, and fibrosis in NASH. In vitro tests revealed that TBC1D25 overexpression restrained NASH responses. Subsequent mechanistic validation experiments demonstrated that TBC1D25 interfered with NASH progression by inhibiting abnormal lipid accumulation and inflammation. TBC1D25 deficiency significantly promoted NASH occurrence and development. Therefore, TBC1D25 may potentially be used as a clinical therapeutic target for NASH treatment.     

HPI在肝癌组织中的表达及其对肝癌细胞特异性抑增殖效应研究

肝细胞增殖抑制因子（Ｈｅｐａｔｉｃｐｒｏｌｉｆｅｒａｔｉｏｎｉｎｈｉｂｉｔｏｒ,ＨＰＩ）粗制品、半纯品和纯品对体外培养的人肝癌细胞具有显著抑增殖作用,随样品纯度提高抑制活性逐渐增强。纯品（浓度５μｇ／ｍｌ）的抑制率达７７．７１％。正常成年大鼠肝细胞呈ＨＰＩ阳性表达。在ＤＥＮ诱发大鼠肝细胞癌的发生发展过程中,转化的癌前期细胞和肝癌细胞呈ＨＰＩ阴性表达。表明肝细胞ＨＰＩ的表达能力在其癌变过程中消失,从而失去了自身的抑癌作用。     

猪肝刺激物质pHSS对离体肝细胞DNA合成的影响

应用[~3H]TdR掺入离体培养大鼠肝细胞DNA的方法,测定由本室提取的pHSS的生物活性。结果表明,pHSS可显著促进原代培养大鼠肝细胞的DNA合成,其促进率约为对照组的10倍左右。培养液中血清浓度对pHSS的生物活性表达有显著影响,不同浓度血清可以使pHSS表现出不同的量效关系,这些结果在Buffello大鼠肝细胞系的实验中得到进一步证实。在低剂量pHSS的刺激下,不同年龄大鼠肝细胞的[~3H]TdR掺入率无显著差异。但高剂量时,pHSS对幼鼠作用不明显。     

L-tryptophan binding to hepatic nuclei: Age and species differences

Summary The present experiments report differences in in vitro nuclear binding affinity for L-tryptophan 1) between livers of young (6 1/2 weeks old) and older (30 weeks old) NZBWF₁ mice, but not so in similar aged Swiss mice, and also, 2) in livers of hamsters compared to livers of guinea pigs. In vitro hepatic nuclear specific binding affinity after tube-feeding L-tryptophan (520mg/100g body weight) to mice 1 h before killing revealed less in young than in older NZWBF₁ mice, comparable to the above in vitro assay studies. In vitro nuclear binding affinity for L-tryptophan of livers of hamsters was significantly less than that of livers of guinea pigs or Swiss mice. In general, the degree of stimulatory effect on hepatic protein synthesis, as measured by in vitro [¹⁴C]leucine incorporation into protein using microsomes of animals tube-fed L-tryptophan 1 h before killing compared to that of animals tubefed water, correlated with the basal nuclear specific binding affinity to L-tryptophan of the animals (ages and species) used.This study was supported by U.S. Public Health Service Research Grant DK-45353 from the National Institute of Diabetes and Digestive and Kidney Diseases.