Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin, an adipocyte-secreted hormone, is one of the central regulators of body weight homeostasis. In humans and rodents, two major forms of leptin receptors (OB-R) are expressed. The short form (OB-RS), considered to lack signaling capability, is detected in many organs. In contrast, OB-R long form (OB-RL) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfection experiments have demonstrated that OB-RL transduces an intracellular signaling similar to interleukin (IL)-6 type-cytokine receptors. To define the specificity by which OB-R induces genes and cooperates with signal transduction pathways utilized by other hormones and cytokines, rat and human hepatoma cell lines were generated which stably express human OB-RL. Hepatoma cell lines selected for appreciable levels of OB-RL mRNA display enhanced leptin binding and responded to leptin with an IL-6 receptor-like signaling that includes the activation of STAT proteins, induction of acute-phase plasma proteins, and synergism with IL-1 and tumor necrosis factor-alpha. A leptin-mediated recruitment of phosphatidylinositol 3-kinase to insulin receptor substrate-2 was also detected. However, no significant tyrosine phosphorylation of insulin receptor substrate-2 and modulation of the immediate cell response to insulin were observed. The data suggest that OB-RL action in hepatic cells is equivalent to that of IL-6 receptor. However, leptin does not play a specific role in muting insulin action on hepatoma cells and therefore may not contribute to the diabetic symptoms associated with obesity.
 ...
PMID:Leptin receptor action in hepatic cells. 919 22

Insulin resistance is associated with hyperleptinemia, whilst exposure of hepatoma cells and isolated adipocytes to high concentrations of leptin has been demonstrated to result in attenuated insulin response and a reduced suppression of gluconeogenesis. To determine the acute metabolic effects of hyperleptinemia, we measured whole body glucose uptake (WBU) and hepatic glucose production rate (HGP) in rats using the euglycemic hyperinsulinemic clamping technique. Anesthetised male rats received recombinant murine leptin (1 microg/min) or vehicle into the jugular vein for 90 min. After 30 min of leptin infusion, insulin was infused to a level of 70 microU/ml and a variable-rate glucose infusion was adjusted to maintain blood glucose levels to 4-4.5 mmol/l. Glucose infusion rates during clamping were not different between leptin-infused and control rats, and there were no significant effects on the HPR or WBU measured using [6-(3)H]glucose under basal or clamped conditions. In summary, our data demonstrate that acute hyperleptinemia in normal weight Wistar rats does not appear to reduce insulin sensitivity, in vivo, or to affect HPR under clamp conditions.
 ...
PMID:Acute hyperleptinemia does not modify insulin sensitivity in vivo in the rat. 966 85

We have examined the role of leptin in tumor-induced anorexia in 2 different tumor models. In rats bearing the Yoshida AH-130 ascites hepatoma, the reduction in food intake becomes important from day 6 after tumor inoculation. Interestingly, at day 4, when the animals do not show any anorectic behavior, circulating leptin levels were already reduced. Indeed, in all the tumor-bearing groups studied the levels of leptin were lower than in control animals. Moreover, the changes in the circulating levels paralleled changes in adipose tissue leptin mRNA expression, even at early stages following tumor inoculation when neither food intake nor fat stores were modified by the presence of a tumor. Interestingly, 7-day pair-fed controls showed changes similar to those present in tumor-bearing rats. These results agree with previous observations relating fasting to decreased leptin expression. Similar results were observed in another tumor model, the mouse Lewis lung carcinoma; i.e., at day 8 after tumor inoculation (when the animals did not show anorexia) both the circulating levels and the adipose leptin mRNA expression were also reduced. Our results suggest that experimental cancer-induced anorexia is not related to leptin changes.
 ...
PMID:Leptin and tumor growth in rats. 1032 24

Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.
 ...
PMID:Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. 1068 12

It is not known whether obesity increases the risk for hepatocellular carcinoma (HCC) simply because it promotes cirrhosis, a general risk factor for HCC, or via some other mechanism that operates independently of cirrhosis. If the latter occurs, then hepatocyte hyperplasia, an early event during the neoplastic process, might begin before liver cirrhosis develops. Genetically obese, leptin-deficient ob/ob mice are models for nonalcoholic fatty liver disease (NAFLD), a type of liver disease that is strongly associated with obesity and type 2 diabetes. Similar to obese, diabetic patients, ob/ob mice have an increased incidence of HCC. However, unlike humans with NAFLD, they rarely, if ever, develop cirrhosis spontaneously. To determine whether the noncirrhotic livers of ob/ob mice with NAFLD exhibit hepatocyte hyperplasia, parameters of proliferation and apoptosis were compared in adult ob/ob mice and their healthy litter mates. Adult ob/ob mice have an increase in liver mass relative to body mass. This hepatomegaly cannot be explained solely by lipid accumulation and is accompanied by significant increases in hepatocyte proliferative activity (as evidenced by increased Erk activation, cell-cycle related gene expression, bromodeoxyuridine incorporation, and hepatic DNA content) with concomitant inhibition of hepatocyte apoptosis (as evidenced by decreased numbers of apoptotic hepatocytes, induction of several antiapoptotic mechanisms, and decreased activation of procaspase 3). Thus, liver hyperplasia is evident at the earliest stage of NAFLD in ob/ob mice, which supports the concept that obesity-related metabolic abnormalities, rather than cirrhosis, initiate the hepatic neoplastic process during obesity.
 ...
PMID:Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? 1143 35

Leptin, an adipocyte-derived hormone, regulates food intake and energy expenditure in the hypothalamus via its receptor, member of the class I cytokine receptor family. Leptin resistance has been observed in rodents and in humans. However, the mechanisms could not be explained in most cases of human obesity, except for rare cases with mutations in the leptin receptor. Recent reports demonstrated that ethanol inhibited the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activated by some members of the class I cytokine receptor family. In this study, we examined the effects of ethanol on the leptin-induced JAK/STAT signaling pathway using human hepatoma cell lines transiently expressing long form of the leptin receptor. A 30 min pretreatment with ethanol dose-dependently inhibited the leptin-induced STAT3 phosphorylation. Furthermore, to determine the time course of ethanol inhibitory effects, the cells were incubated in 10 mM ethanol for various times. Partial inhibition of leptin-induced STAT3 activation was seen after 1 min of treatment with ethanol and completely inhibited after 30 min pretreatment. SB 202190, a p38 mitogen-activated protein kinase (MAPK) inhibitor, partly prevented this inhibition by ethanol of leptin-induced STAT3 activation. These findings suggest that ethanol time- and dose-dependently inhibits the leptin action, in part via p38 MAPK.
 ...
PMID:Ethanol inhibits leptin-induced STAT3 activation in Huh7 cells. 1216 72

In chickens, leptin is expressed mainly in the liver, where its receptor gene expression has also been reported, and in adipose tissue. In view of the key role played by the liver in lipogenesis in avian species, the hepatic expression of leptin may have physiological significance. In this study, we showed that leptin is constitutively expressed and secreted in a chicken-derived hepatoma cell line (LMH). Although insulin regulates leptin expression in vivo, incubation of LMH cells in the presence of 100 nM insulin for 24 or 48 h had no effect on leptin expression or its secretion in the culture medium. In addition, we developed a specific chicken leptin receptor real-time reverse transcription (RT)-PCR, and downregulation of leptin receptor gene expression by homologous and heterologous signals was demonstrated, as relative leptin receptor mRNA levels were significantly decreased after exposure of LMH cells to recombinant chicken leptin or porcine insulin. In conclusion, our results indicate that leptin is probably able to desensitize its own response in the chicken liver. Finally, the ability of insulin and leptin to regulate chicken leptin receptor gene expression suggests a direct role of leptin in the control of hepatic metabolism.
 ...
PMID:Leptin and insulin downregulate leptin receptor gene expression in chicken-derived leghorn male hepatoma cells. 1460 35

Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance.
 ...
PMID:Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression. 1497 21

Elevated secretion of glucocorticoids (GCs) or hypersensitivity to GCs has a permissive effect on the development of obesity and leads to abnormalities of body fat distribution. Recent studies demonstrated GCs act as antagonists of leptin in rodents. However, little is known about the interaction between GCs and leptin signaling. In the present study, we investigated the effects of GCs on leptin action in vitro and in vivo. GCs rapidly inhibited the leptin-induced STAT3 phosphorylation in a dose- and time-dependent manner, as assayed by Western blotting using anti-phosphospecific-STAT3 in human hepatoma cell lines (Huh7) transiently expressing long form leptin receptor. GCs also inhibited the leptin-induced JAK2 tyrosine phosphorylation but unaltered the specific binding of (125)I-leptin to the cells. Parallel experiments, however, demonstrated that the inhibitory effects of GCs were not observed in either IL-6- or LIF-induced STAT3 phosphorylation. Furthermore, we examined the feeding behavior and hypothalamic leptin signaling following intracerebroventricular (icv) infusion of GCs prior to icv leptin infusion in Sprague-Dawley rats. The food intake after 24 h of icv leptin injection increased 3-fold in GCs-treated animals. In addition, central infusion of GCs resulted in a marked reduction of hypothalamic STAT3 phosphorylation in response to icv infusion of leptin. To clarify the molecular mechanism by which GCs rapidly reduce leptin-induced JAK/STAT signaling, we examined the intracellular signal transduction pathway potentially mediated by GCs. PD98059, a specific MEK inhibitor, blocked the inhibitory effects of GCs on leptin-induced JAK/STAT activation in Huh7 cells. These results suggest GCs antagonize leptin action by a rapid inhibition of the leptin-induced JAK/STAT pathway partly via MAPK cascade.
 ...
PMID:Rapid inhibition of leptin signaling by glucocorticoids in vitro and in vivo. 1499 17

Apolipoprotein M (apoM) is a novel apolipoprotein presented mostly in high-density lipoprotein (HDL) in human plasma. Previously we have reported that both leptin and leptin receptor are essential for apoM expression in vivo. The expression of apoM is lower in the leptin deficient (ob/ob) mouse and leptin receptor deficient (db/db) mouse than in the normal mouse. In the present study, however, we demonstrated that supra-physiological concentrations of recombinant leptin significantly inhibited apoM transcription and secretion in the human hepatoma cell line, HepG2 cells. Both Northern blotting and real-time RT-PCR were applied into the analyses of apoM mRNA levels, and compatible data were obtained. The inhibitory effect of leptin on apoM mRNA levels in HepG2 cells is dose dependent, i.e. 100 ng/mL of leptin decreased apoM mRNA levels by 30%, and 500 ng/mL of leptin decreased apoM mRNA levels about 50%. Even at a physiological concentration of leptin (10 ng/mL), apoM expression was decreased, and in parallel, the secretion of apoM into the medium was also decreased. Furthermore, we examined apoAI, apoB and apoE by Northern blotting analyses. The results demonstrated that leptin does not significantly influence the expressions of apoAI, apoB and apoE in HepC2 cells, suggesting that leptin has a specific regulatory effect on hepatic apoM transcription and secretion in vitro. The mechanism on the contradictory effects of leptin on apoM expression in vivo and in vitro needs further investigation.
 ...
PMID:Leptin inhibits apolipoprotein M transcription and secretion in human hepatoma cell line, HepG2 cells. 1590 76


1 2 3 4 5 6 7 8 Next >>