Hepatoportal Region Research Articles

Lipopolysaccharide-mediated effects of the microbiota on sleep and body temperature

Recent research suggests that microbial molecules translocated from the intestinal lumen into the host’s internal environment may play a role in various physiological functions, including sleep. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, and lipoteichoic acid, a cell wall component of gram-positive bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Building upon these findings, we aimed to explore the sleep signaling potential of intraportally administered lipopolysaccharide (LPS), a primary component of gram-negative bacterial cell walls, in rats. Low dose of LPS (1 μg/kg) increased sleep duration and prolonged fever, without affecting systemic LPS levels. Interestingly, administering LPS systemically outside the portal region at a dose 20 times higher did not affect sleep, indicating a localized sensitivity within the hepatoportal region for the sleep and febrile effects of LPS. Furthermore, both the sleep- and fever-inducing effects of LPS were inhibited by indomethacin, a prostaglandin synthesis inhibitor, and replicated by intraportal administration of prostaglandin E2 or arachidonic acid, suggesting the involvement of the prostaglandin system in mediating these actions.

The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide

Microbial molecules translocated from the intestinal lumen into the host’s internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.

A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings.

Background & AimsDisturbances of the enterohepatic circulation of bile acids (BAs) are seen in a number of clinically important conditions, including metabolic disorders, hepatic impairment, diarrhea, and gallstone disease. To facilitate the exploration of underlying pathogenic mechanisms, we developed a mathematical model built on quantitative physiological observations across different organs.MethodsThe model consists of a set of kinetic equations describing the syntheses of cholic, chenodeoxycholic, and deoxycholic acids, as well as time-related changes of their respective free and conjugated forms in the systemic circulation, the hepatoportal region, and the gastrointestinal tract. The core structure of the model was adapted from previous modeling research and updated based on recent mechanistic insights, including farnesoid X receptor–mediated autoregulation of BA synthesis and selective transport mechanisms. The model was calibrated against existing data on BA distribution and feedback regulation.ResultsAccording to model-based predictions, changes in intestinal motility, BA absorption, and biotransformation rates affected BA composition and distribution differently, as follows: (1) inhibition of transintestinal BA flux (eg, in patients with BA malabsorption) or acceleration of intestinal motility, followed by farnesoid X receptor down-regulation, was associated with colonic BA accumulation; (2) in contrast, modulation of the colonic absorption process was predicted to not affect the BA pool significantly; and (3) activation of ileal deconjugation (eg, in patents with small intestinal bacterial overgrowth) was associated with an increase in the BA pool, owing to higher ileal permeability of unconjugated BA species.ConclusionsThis model will be useful in further studying how BA enterohepatic circulation modulation may be exploited for therapeutic benefits.

Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats.

Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.

Negative feedforward control of body fluid homeostasis by hepatorenal reflex

The liver, well known for its role in metabolism, clearance and storage can also be regarded as a sensory organ. The liver is an ideal place to monitor the quality and quantity of absorbed substances, because portal blood delivers substances absorbed from the intestine to the liver and these substances circulate in the hepatic vasculature before substances enter the systemic circulation. Sodium (Na(+))-sensitive mechanism exists in the liver; it is stimulated by the increase in Na(+) concentration in the portal vein, and then hepatorenal reflex is triggered. Renal sympathetic nerve activity is reflexively decreased and urinary Na(+) excretion is increased. This Na(+)-sensitive hepatorenal reflex has a significant role in post-prandial natriuresis. However, the long-term role of this reflex in Na(+) homeostasis may be less important, probably because of the desensitization of Na(+)-sensitive mechanisms. Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) is involved in the hepatoportal Na(+)-sensitive mechanism, and NKCC1 expression is reduced if the hepatoportal region is exposed to high Na(+) concentrations for a long time. This situation occurs when animals intake a high-sodium chloride diet for a long time. Liver cirrhosis also impairs the Na(+)-sensitive hepatorenal reflex. Hepatoportal baroreceptor-induced renal sympathetic excitation and the impaired Na(+)-sensitive hepatorenal reflex may partially explain the Na(+) retention in liver cirrhosis.

Hepatoportal Leptin Sensors and Their Reflex Effects on Autonomic Outflow in the Rat

Afferent nerve signals were recorded from a peripheral cut end of the small nerve bundle of the hepatic branch of the vagus nerve in anesthetized rats. An injection of leptin (100 pg, 0.1 mL) into the portal vein facilitated the afferent activity. The response was dose dependent. Further, an intravenous (IV) injection of leptin (1 ng, 0.1 mL) facilitated the efferent nerve activity of the sympathetic nerve to the adrenal gland and suppressed that of the celiac branch of the vagus nerve. In hepatic vagotomized rats, no change in efferent activity of the adrenal sympathetic nerve nor celiac branch of the vagus nerve was observed following iv administration of leptin. These observations suggest that leptin sensors in the hepatoportal region play a role in reflex modulation of autonomic outflow in relation to metabolic functions.

Central Versus Peripheral Glucose Sensing and the Response to Hypoglycemia

One of the most significant limits in our ability to tightly control blood glucose in patients with diabetes is the occurrence of hypoglycemia. It is now clear that when blood glucose drops in a normal individual, there is a rapid and well-coordinated endocrine response (1). Glucagon, epinephrine, norepinephrine, cortisol, and growth hormone levels rise as the glucose level falls (1). The combination of low blood glucose and elevated hormones limits glucose utilization by the tissues of the body and stimulates glucose production by the liver (2). As a consequence of these metabolic adjustments, the fall in blood glucose is limited and the ensuing hypoglycemia is minimized. In an individual with diabetes, the glucagon response to hypoglycemia begins to diminish relatively early in the disease process (1). Later, even the sympatho-adrenal response may become limited (1). As a consequence, individuals with diabetes, particularly type 1 diabetes, are at increased risk for serious hypoglycemia. Understanding more about the normal response to hypoglycemia and about the failure of the normal response in diabetic individuals is thus of great importance. A recent debate in this area relates to the site of hypoglycemic sensing. While it has long been known that the brain is involved in detecting low blood glucose, data began to appear in the early 1990s supporting the view that hypoglycemic sensing was also occurring at peripheral sites, particularly within the hepato-portal region. A series of articles by Donovan and …

Mechanism of rapid-phase insulin response to elevation of portal glucose concentration

The hepatoportal region is important for glucose sensing; however, the relationship between the hepatoportal glucose-sensing system and the postprandial rapid phase of the insulin response has been unclear. We examined whether a rapid-phase insulin response to low amounts of intraportal glucose infusion would occur, compared that with the response to intrajugular glucose infusion in conscious rats, and assessed whether this sensing system was associated with autonomic nerve activity. The increases in plasma glucose concentration did not differ between the two infusions at 3 min, but the rapid-phase insulin response was detected only in the intraportal infusion. A sharp and rapid insulin response was observed at 3 min after intraportal infusion of a small amount of glucose but not after intrajugular infusion. Furthermore, this insulin response was also induced by intraportal fructose infusion but not by nonmetabolizable sugars. The rapid-phase insulin response at 3 min during intraportal infusion did not differ between rats that had undergone hepatic vagotomy or chemical sympathectomy with 6-hydroxydopamine compared with control rats, but this response disappeared in rats that had undergone chemical vagotomy with atropine. We conclude that the elevation of glucose concentration in the hepatoportal region induced afferent signals from undetectable sensors and that these signals stimulate pancreas to induce the rapid-phase insulin response via cholinergic nerve action.

흰쥐의 종양에 대한 단삼 추출물의 항종양 활성

The present study was carried out to investigate the antitumor activity of Salvia miltiorrhiza (SM) herbal extract in rat tumor model. We used a new tumor animal model for the invasion and metastasis of cancer using genetically k-ras-induced rat kidney cells (RK3E-ras). We observed tumor as early as 7 days after the injection of RK3E-ras cells in subcutaneous of Sprague-Dawley rats. All of the rats developed tumor mass at the inoculated site. After 7 days, the experimental groups were divided into two: saline control and injected with SM (200 mg/kg) groups. We investigated tumor`s weight, size and hepatic metastasis of each group. Injection of SM herbal extract every other day for 14 days significantly inhibited tumor growth. Histologically, the tumors were undifferentiated carcinoma showing multifactorial necrosis and hemorrhage; also, the tumor invaded into hepatoportal region. Treatment with SM herbal extract caused significant inhibition of tumor cell proliferation. Our data showed that SM herbal extract is effective in controlling the tendency of tumor cell proliferation and metastasis by injection of RK3E-ras cells. These findings provided the potential value of SM as a novel antitumor agent candidate.

Role Played by Vagal Chemical Sensors in the Hepato-portal Region and Duodeno-intestinal Canal: An Electrophysiological Study

Role Played by Vagal Chemical Sensors in the Hepato-portal Region and Duodeno-intestinal Canal: An Electrophysiological Study

Effects of High NaCl Diet on Arterial Pressure in Sprague-Dawley Rats with Hepatic and Sinoaortic Denervation

The Na(+) receptor that exists in the hepatoportal region plays an important role in postprandial natriuresis and the regulation of Na(+) balance during NaCl load. Thus it would be considered that a dysfunction of the hepatic Na(+) receptor might result in the elevation of arterial pressure under a condition of high NaCl diet. To elucidate this hypothesis, arterial pressure was continuously measured during three weeks of high NaCl diet (8% NaCl) in four groups of rats: (i) intact rats, (ii) rats with hepatic denervation (HD), (iii) rats with sinoaortic denervation (SAD), and (iv) rats with SAD+HD. During a 1-week normal NaCl diet period, there was no difference in arterial pressure among the four groups. A high NaCl diet had no influence on arterial pressure in intact or HD rats; however, it significantly increased by 11 +/- 3 mmHg in SAD rats. The addition of HD to SAD had no synergistic effect on arterial pressure; i.e., in SAD+HD rats, mean arterial pressure increased by 13 +/- 1 mmHg. In conclusion, sinoaortic baroreceptor, but not hepatic Na(+) receptor, has a significant role in the long-term regulation of arterial pressure on a high NaCl diet.

Separation of hepatic and gastrointestinal signals from the common "hepatic" branch of the vagus.

Anatomic studies show that the common hepatic branch (CHB) of the vagus contains afferent fibers that innervate sites outside the hepatoportal region, primarily in the gastrointestinal tract. In the current experiments on the anesthetized rat, the source of signals from the CHB was determined by recording CHB neurophysiological responses before and after transection of the gastroduodenal branch (GDB) of the CHB. Serotonin [5-hydroxytryptamine (5-HT)] and CCK-8 were used as probes to stimulate the CHB. Most of the CHB afferent fibers were 5-HT sensitive (56%), and 35% of these were also sensitive to CCK-8. Portal vein vs. jugular vein infusion of 5-HT and CCK-8 and GDB transection showed that 5-HT- and CCK-sensitive fibers innervate the hepatoportal region and areas outside the hepatic hilus (e.g., the gastrointestinal tract). Suppression of basal nerve activity by a 5-HT(3) receptor antagonist (Y-25130) suggests that approximately 50% of CHB afferent fibers contain 5-HT(3) receptors, but none of these fibers appears to be in the hepatoportal region because only in rats with an intact GDB did Y-25130 reduce nerve activity. In summary, these data are in close agreement with anatomic observations on the distribution of the CHB fibers and indicate that neurophysiological studies of the CHB must be carefully evaluated given the prominent role of nonhepatoportal afferent signals recorded from the CHB.

Hepato-vagal pathway associated with nicotine's anorectic effect in the rat

Nicotine reduces appetite and body weight. Because the hepato-portal area senses different types of nutrients that transmit signals via vagal afferent nerves to the hypothalamus to modify food intake and feeding pattern, we investigated the effect of nicotine on a hepato-vagal–hypothalamic pathway. Low doses of nicotine (<10 ng) injected into portal vein (ipv) decreased, while high doses of nicotine increased (≥10 ng) electrophysiological activity of hepatic vagal afferents. Stimulatory effect of high dose of nicotine on vagal hepatic afferents was blocked by a prior ipv injection of curare (30 μg) or hexamethonium (1 mg). Furthermore, activities of gastric vagal and adrenal sympathetic efferents were suppressed by low-dose, but stimulated by high-dose ipv nicotine. These reflex effects did not occur in hepatic vagotomized rats. Results of experiments demonstrate that in addition to nicotine's anorectic effect being mediated via a direct central action, nicotine also acts peripherally via hepatic vagal afferents from sensors of nicotine in the hepato-portal region.

Effect of lysine on afferent activity of the hepatic branch of the vagus nerve in normal and l-lysine-deficient rats

Amino acid deficiency was modeled by feeding rats a diet deficient in the essential l-amino acid, l-lysine ( l-lys). There is a rapid anorectic response to such a diet, and a strong preference for l-lys develops during the deficiency. While the brain appears to trigger this preference, the peripheral pathways that inform the brain about the deficiency are not well understood. One possible information pathway may utilize an “amino acid sensor” in the hepatoportal region. In the present study, we measured in vivo neural activity in normal and l-lys-deficient rat. Compared to the normally fed controls, we found an approximately 100-fold increase in the firing sensitivity of the l-lys sensors in vagal afferent fibers from the hepatoportal region of the l-lys-deficient rats. Injection of 10 mM l-lys into the hepatoportal circulation, but not d-lysine ( d-lys), evoked an increase in afferent activity. While l-lys deficiency enhanced the sensitivity of the l-lys sensors, the sensitivity due to other small amino acid sensors remained unchanged. Finally, we observed a time-dependent response of the lysine sensors to lysine deficiency. It required 3–4 days of maintenance on the lysine-deficient diet for the sensitivity of the l-lys sensors to change. Taken together, these results provide additional data to support the existence of putative l-amino acid sensors in the hepatoportal circulation. Additionally, they describe several characteristics of the l-lys sensors and show that these sensors may contribute to the adaptation to dietary l-lys deficiency and to maintenance of l-amino acid homeostasis.

Hepatoportal bumetanide-sensitive K(+)-sensor mechanism controls urinary K(+) excretion.

To determine whether a K(+)-sensor mechanism exists in the hepatoportal region, periarterial hepatic afferent nerve activity responses to intraportal injection of KCl were examined in anesthetized rats. Hepatic afferent nerve activity increased in response to intraportal injection in a K(+) concentration-dependent manner, and the increase was attenuated by inhibition of the Na(+)-K(+)-2Cl(-) cotransporter by bumetanide in a dose-dependent manner. These results suggest that a bumetanide-sensitive K(+)-sensor mechanism exists in the hepatoportal region. Stimulation of this mechanism by intraportal KCl infusion elicited an immediate and powerful kaliuresis with no significant change in the plasma K(+) concentration; this was significantly greater than the kaliuresis induced by intravenous KCl infusion and was attenuated by severing the periarterial hepatic nervous plexus. These results indicate that a hepatoportal bumetanide-sensitive K(+)-sensor mechanism senses the portal venous K(+) concentration and that stimulation of this sensor mechanism causes kaliuresis, which is mainly mediated by the periarterial hepatic nervous plexus.

Reflex Effects of Oral, Gastrointestinal and Hepatoportal Glutamate Sensors on Vagal Nerve Activity

Glutamate sensors in the oral cavity, gastrointestinal canal and hepatoportal region are thought to function in the reflex regulation of vagal activity to the gastrointestinal tract and pancreas. In support of this notion, the findings summarized in this report demonstrate that the infusion of monosodium glutamate (MSG) into the stomach (150 mmol/L, 3 mL), duodenum (150 mmol/L, 3 mL) and portal vein (10 mmol/L, 0.1 mL) increases afferent activity in the vagal gastric, celiac and hepatic nerves, suggesting the existence of glutamate sensors in the gastric wall, intestinal wall and hepatoportal region. Further, oral, gastric and intestinal infusions of MSG (150 mmol/L, isotonic solution) and the infusion of MSG (10 mmol/L, 0.1 mL) into the portal vein resulted in reflex activation of the efferent gastric and pancreatic branches of the vagus. The intravenous injection of 10 mmol/L MSG (0.1 mL) also induced a reflex activation of the efferent discharges of the gastric branch of the vagus; however, in hepatic and celiac vagotomized rats, the intravenous injection of MSG (1 or 3mol/L, 1 mL) produced no effect on gastric vagal activity. The results of these experiments demonstrate the importance of the afferent nerve signals from visceral glutamate sensors in generating the reflex activation of gastrointestinal and pancreatic functions in response to MSG administration.

Effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve

The effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve was investigated in the rat. Intravenous infusion of 1 or 2 ng melatonin resulted in a decrease, and 10 or 20 ng or larger amount of melatonin caused an increase in the efferent activity of the adrenal nerve. The least effective dose for the suppressive activity of melatonin was 100 pg and the response is dose-related. Administration of either 1 ng or 10 ng of melatonin did not change the plasma glucose concentration until 30 min after the administration. Hepatic vagotomy eliminates the inhibitory effect of melatonin. These results suggest that melatonin sensors in the hepato-portal region and melatonin receptors in the SCN play important roles in the regulation of sympathetic outflow to the adrenal medulla.

Hepatorenal and Hepatointestinal Reflexes in Sodium Homeostasis

Hepatorenal and hepatointestinal reflexes with receptors in the hepatoportal region transduce portal plasma Na+ concentration into hepatic afferent nerve activity and reflexively augment renal Na+ excretion and attenuate intestinal Na+ absorption before a measurable increase in systemic Na+ concentration. These reflexes contribute to Na+ homeostasis in a negative, "feedforward" fashion.

An Electrophysiological Study on Amino Acid Sensors in the Hepato‐Portal System in the Rat

The existence of amino acid sensors sensitive to arginine, alanine, leucine and glycine in the hepato-portal region was previously reported based on recording of the afferent signals from the hepatic branch of the vagus nerve. The present study was carried out to investigate the effects of fifteen different amino acids on the activity of the vagal hepatic afferents. Intraportal administration (10 mM, 0.1 mL) of alanine, arginine, histidine, leucine, lysine, serine, tryptophane and valine increased vagal afferent discharge rate, and that of cysteine, glycine, isoleucine, methionine, phenylalanine, proline and threonine suppressed it. The results indicate the existence of two groups of amino acids sensors which exhibit excitatory or inhibitory effect on the afferent activity of the hepatic branch of the vagus nerve. The change in afferent activity to the hypothalamus may affect reflex regulation of the visceral functions and thereby influence appetite.

Reflex control of renal nerve activity originating from the osmoreceptors in the hepato-portal region

The reflex effects of hepatic osmoreceptors on the renal sympathetic nerve activity (RNA) were studied in 30 pentobarbital anesthetized, vagotomized and sino-aortic baroreceptor denervated (SAD + VD) rabbits. The changes in mean arterial pressure (MAP), heart rate (HR), and RNA were examined when 9% NaCl, 6.5% LiCl or 50% glucose solution was infused into the hepatic portal vein at a rate of 0.15 ml/kg/min for 10 min. Infusion of 9% NaCl solution into the hepatic portal vein increased the plasma osmolality by 10.8 ± 1.0 mOsmol/kg from the control level in the blood of the hepatic portal vein and by 2.8 ± 2.0 mOsmol/kg from the control level in the systemic blood. MAP was significantly elevated by 10.2 ± 5.0 mmHg but HR did not change with hepatic portal infusion of 9% NaCl solution. Intraportal infusion of 9% NaCl solution significantly decreased the RNA by 28.6–34.2% from the control level, 6.5% LiCl solution by 28.6 ± 4.7%, and 50% glucose solution by 26.2 ± 3.0%. Femoral arterial infusion of hypertonic NaCl solution, however, did not evoke any significant change in RNA in SAD + VD rabbits. These findings suggest that increases in osmolality and NaCl concentration in the systemic circulation do not result in a decrease of RNA. Furthermore, after section of the anterior and posterior plexus of the hepatic nerve, hepatic portal infusion of hypertonic NaCl solution elicited no change in RNA. The present data indicate that an increase in osmolality in the hepatic portal venous blood results in a reflex decrease of RNA. This reflex may be important for restoration of a postprandial increase in osmolality.