Characteristics And Mechanisms Of Hepatic Glucose And Fatty Acid Metabolism In Rats During High Altitude Acclimatization

BackgroundFollowing the increase of immigrant population and business activities in high altitude, how to adapt to lower pressure lower oxygen of the plateau and decrease the incidence of acute mountain sickness becomes a critical problem that researchers are facing. The important points to high altitude acclimatization are how to maintain the balance of energy metabolism and how to use energy substances efficiently. Liver play a key role in regulation of energy metabolism in body. In this present study, we discussed the characterisitics and mechanisms of glucose and fatty acid metabolism in liver during high altitude acclimatization. Meanwhile, we might indirectly understand those characterisitics and mechanisms in body through the changes in liver.ObjectiveHigh altitude (HA) affects energy metabolism. The impact of acute and chronic HA acclimatization on the major metabolic pathways is still controversial. We aimed to evaluate the characteristics and mechanisms of hepatic glucose and fatty acid (FA) metabolism in rats during HA acclimatization. Rats were exposed to an altitude of4,300m for30days and the expressions of some key proteins involved in glucose and FA metabolism, as well as their metabolites in the liver and the plasma were measured after acclimatization for1to30days.MethodsThirty six male SD rats (body weights:220-300g) were randomly assigned into six groups respectively named H1(n=6, HA exposure for1day), H3(n=6, HA exposure for3days), H7(n=6, HA exposure for7days), H15(n=6, HA exposure for15days), H30(n=6, HA exposure for30days), and C (n=6, no HA exposure, controls). Rats were given the standard rodent chow and water ad libitum. Following overnight fasting, rats were sacrificed under anaesthesia with10%chloral hydrate (0.4ml/100g body weight, i.p). Blood samples were collected from each rat into the heparinized tubes, and plasma was collected for the measurement of free fatty acid (FFA) and lactate by spectrophotometry, blood glucose and alanine aminotransferase (ALT) by automatic biochemical analyzer. The liver tissues were snap-frozen in liquid nitrogen. The mRNA and protein levels of four key factors involved in hepatic glucose metabolism (isocitrate dehydrogenase, ICDH; Glucose-6-phosphatase, G6Pase; AMP activated kinase, AMPK and forkheadbox01, FoxO1), four key factors involved in FA metabolism (carnitine palmitoyl transferase-I, CPT-I; peroxisome proliferation-activated receptors a, PPARa; acetyl CoA carboxylase-1, ACC-1and AMPK) were examined by real time PCR and Western blot. G6Pase, FoxO1and AMPK are related to gluconeogenesis, ICDH is a key rate-limiting enzyme in the Krebs cycle involved in ATP production; CPT-I and PPARa are associated with FA oxidation, while ACC-1and AMPK are related to FA synthesis. The hepatic levels of lactate, ATP and glycogen were detected by spectrophotometry, and the level of hepatic total ketone body was measured by ELISA.ResultsWe observed no significant difference in the blood levels of ALT, FFA, lactate, and glucose between the rats exposed to an altitude of4,300m and those without HA exposure. Acute exposure (1-7days) of rats to HA led to a marked reduction in bodyweight and food intake, in contrast to an increase in these parameters when an extended exposure to HA accomplished. In addition, acute exposure of rats to HA was found to significantly alter the hepatic expressions of the following genes, proteins and metabolites involved in glucose metabolism:(1) increased expression level of ICDH (days1,3, and7) and reduced ATP content (day1);(2) increased levels of G6Pase and glycogen (days1,3, and7);(3) decreased expressions of AMPK and FoxO1throughout the whole experimental period. However, the levels of AMPK and FoxO1showed a trend of increase after Day15and the levels of these two factors in H30group were higher than those in H15group. The expression of hepatic ICDH, G6Pase, glycogen and ATP returned to the control level in rats following chronic exposure (days15and30). Meanwhile, we didn’t find significant change in hepatic lactate content during the whole experimental period.Similarly, acute exposure of rats to HA led to significant changes in the hepatic expressions of the following genes, proteins and metabolites involved in FA metabolism:(1) increased expressions of CPT-I and PPARa, as well as increased production of total hepatic ketone body (day3); and (2) increased ACC-1level (days1and3). Longer exposure (>15days) caused a marked decrease in the expression of CPT-I and PPARa. By30days after HA exposure, the expression levels of CPT- I and PPARa, as well as ACC-1returned to the control level.ConclusionsIncreased hepatic gluconeogenesis, glycogen synthesis, ketogenesis, FA oxidation and synthesis in the early phase of HA exposure may be among the important mechanisms for the rats to respond to the hypoxic stress in order to acclimatize themselves to the stressful environments. FoxO1and PPARa were involved in the regulation of hepatic gluconeogenesis and FA oxidation respectively, while AMPK played an important role in both hepatic gluconeogenesis and FA synthesis. Glycogen content increased in liver may depress the activity of AMPK.