Enterohepatic Axis Research Articles

Regulation of hepatic cholesterol metabolism in the rat in vivo: effect of a synthetic fat-free diet on sterol synthesis and low-density lipoprotein transport.

A synthetic fat-free diet, previously shown to decrease hepatic cholesterol synthesis, was utilized to manipulate cholesterol balance in vivo in female Sprague-Dawley rats. A significant 65% decrease of hepatic cholesterol synthesis compared to controls was shown after 1 week of treatment, which remained constant during the following 3 weeks. The inhibitory effect of the diet was completely abolished by cholestyramine supplementation. At week 3 of the experimental diet, bile acid synthesis was reduced by 63%, this reduction being correlated with decreased recycling frequency of the bile acid pool. Hepatic clearance of low-density lipoprotein (LDL) was slightly decreased, with no changes in plasma cholesterol, hepatic LDL-cholesterol uptake and whole body LDL-cholesterol production. When cholesterol and saturated fatty acids were supplemented to the diets in the attempt to disclose alteration in LDL transport, LDL clearance was unaffected; plasma LDL-cholesterol and hepatic LDL-cholesterol uptake were increased, as a consequence of increased LDL-cholesterol production. On the other hand, hepatic cholesterol synthesis was further suppressed; bile acid synthesis was increased by cholesterol supplementation in the fat-free group, even if to subnormal levels. These findings suggest that: (1) bile acid synthesis is decreased by feeding a synthetic fat-free diet, probably due to slower recirculation of bile acids along the entero-hepatic axis in conditions of reduced functional need; (2) consequently, a significant reduction of hepatic cholesterol synthesis is observed with no changes in LDL-cholesterol uptake; (3) further supplementation of dietary cholesterol and saturated fats is compensated for by changes in the rates of cholesterol and bile acid synthesis, but not of LDL transport. The data confirm the existence of independent regulation for hepatic sterol synthesis and LDL transport in this species.

Effects of somatostatin on gastrointestinal hormone-induced glycogenolysis and gluconeogenesis in cultured liver cells.

When isolated rat liver cells were incubated for 15 min in the presence of vasoactive intestinal peptide, gastric inhibitory polypeptide, secretin or glucagon at a concentration of 2.0 micrograms/ml, glycogenolysis was stimulated by 30%-67% above the control. Slight but significant increase on gluconeogenesis was also observed by the addition vasoactive intestinal peptide, gastric inhibitory polypeptide or secretin. Somatostatin inhibited both glycogenolysis and gluconeogenesis induced by these hormones, but the degrees of inhibition are clearly much higher in the hormone-induced gluconeogenesis than glycogenolysis, and no significant inhibition of glycogenolysis was observed in case of glucagon and VIP. These results suggest the possibility that the so-called enterohepatic axis may play a part of roles in the regulation of serum glucose levels through gastrointestinal hormones belonging to the secretin family, and that it may be further regulated by somatostatin through gluconeogenesis.

Effects of vasoactive intestinal peptide on glycogenolysis in cultured liver cells.

When isolated rat liver cells were incubated in the presence of vasoactive intestinal peptide at the concentrations ranging from 0.2 microgram to 2 micrograms per ml, glycogenolysis was maximally stimulated within 15 min. However, somatostatin inhibited the liver glycogenolysis. The combined addition to the incubation medium showed that insulin and somatostatin inhibited the stimulated glycogenolysis induced by vasoactive intestinal peptide, while vasoactive intestinal peptide plus secretin showed no additive effect on glycogenolysis, as compared with single the addition of vasoactive intestinal peptide. On the other hand, the additon of glucagon to vasoactive intestinal peptide showed additive effects on glycogenolysis. These results suggest that the receptor site for vasoactive intestinal peptide may be distinguishable from that for glucagon. Extracellular calcium ions were demonstrated to play an important role in the modulation of vasoactive intestinal peptide-induced glycogenolysis. The evidence presented in this paper indicates that glucose metabolism may be partly regulated by the direct action of vasoactive intestinal peptide on hepatocytes, which is referred to as an enterohepatic axis and that the axis is inhibited by insulin and somatostatin.

Effects of Gastrointestinal and Related Hormones on Glycogenolysis and Gluconeogenesis in Cultured Liver Cells1

When isolated rat liver cells were incubated for 15 min in the presence of vasoactive intestinal peptide, secretin, gastrin, caerulein or glucagon at concentrations ranging from 0.2 microgram to 2 microgram per ml, glycogenolysis was stimulated. Among the gastrointestinal hormones or peptides tested, vasoactive intestinal peptide had the highest stimulatory activity. However, somatostatin was inhibitory for liver glycogenolysis. Combination experiments showed that somatostatin also inhibited the stimulatory effects of vasoactive intestinal peptide and secretin, but not that of glucagon, while glucagon and vasoactive intestinal peptide, or glucagon and secretin showed additive effects on glycogenolysis, but secretin and vasoactive intestinal peptide did not. The results suffest that the receptor site of glucagon is different from those of secretin and vasoactive intestinal peptide. Slight but significant stimulation of gluconeogenesis was also observed by vasoactive intestinal peptide and secretin. The evidence presented in this paper indicates that the so-called enterohepatic axis, in which a part of serum glucose levels is regulated directly by gastrointestinal hormones, exists and that the axis is inhibited by somatostatin.