Hepatic uptake of amino acids in late-pregnant rats. Effect of food deprivation.
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ABSTRACT:
SUBMITTER: Casado J
PROVIDER: S-EPMC1148507 | biostudies-other | 1987 Nov
REPOSITORIES: biostudies-other
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Project description:Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats. Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD) 10, 14 and 19, and postnatal days (PND) 1, 7, 14 and 21. Total bile acids were determined by the enzymatic method, total RNA was isolated and subjected to real time RT-PCR analysis. Liver protein was extracted for western-blot analysis. Results. Under physiological conditions hepatic bile acids were not elevated during pregnancy but increased during lactation in rats. Bile acid synthesis rate-limiting enzyme Cyp7a1 was unchanged on gestational days, but increased on PND14 and 21 at mRNA and protein levels. Expression of Cyp8b1, Cyp27a1 and Cyp7b1 was also higher during lactation. The mRNA levels of small heterodimer partner (SHP) and protein levels of farnesoid X receptor (FXR) were increased during pregnancy and lactation. Bile acid transporters Ntcp, Bsep, Mrp3 and Mrp4 were lower at gestation, but increased during lactation. Hepatic Oatp transporters were decreased during pregnancy and lactation. Conclusion. Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp3 and Mrp4.
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Project description:The present study tested the hypothesis that the liver lipid-lowering effect of insect meal (IM) is caused by its low methionine concentration. A total of fifty, male obese Zucker rats were randomly assigned to five groups of 10 rats each (casein (C), IM, IM + Met, IM + Cys, and IM + EAA). While group C received a diet with casein, the IM-fed groups received a diet with IM as the protein source. In groups IM + Met, IM + Cys and IM + EAA, the diets were additionally supplemented with methionine, cysteine and essential amino acids (EAA), respectively. Hepatic concentrations of triacylglycerols and cholesterol, and hepatic mRNA levels and activities of lipogenic and cholesterogenic enzymes were markedly lower in the IM-fed groups than in group C (p < 0.05). All of these parameters either did not differ across the IM-fed groups or were only slightly higher in groups IM + Met, IM + Cys and IM+EAA than in the group IM. In conclusion, the results indicate that a difference in the amino acid composition between IM and casein, a low concentration of methionine in IM and a reduced cysteine synthesis secondary to a decreased methionine availability resulting from feeding IM are not causative for the lipid-lowering effect of IM.
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Project description:We have studied the role of substrate availability on net L-lactate uptake by liver of anaesthetized fed and 24 h-fasted rats. L-Lactate was infused through a mesenteric vein at infusion rates equivalent to 0, 0.125, 0.25 and 0.5 times the basal turnover rate (Rt). By these means we were able to increase L-lactate portal concentrations up to 5.5 mM, without significant changes in portal pH. In the basal state (0 Rt), a net L-lactate uptake by liver was found in 24 h-fasted animals. No net balance was observed in fed rats. Infusion of L-lactate in fed animals failed to induce a net hepatic uptake, except when L-lactate levels in portal vein were raised above 5 mM. In fasted animals, net L-lactate uptake by liver increased linearly (r = 0.99) as a function of L-lactate concentration in the portal vein, even beyond the saturation of its specific carrier. It is concluded that, first, the L-lactate carrier does not limit net L-lactate uptake, and second, that substrate availability is an important factor modulating net L-lactate uptake by liver.
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Project description:Hepatic availability and uptake of amino acids were measured in fed virgin and 15-day-lactating rats. Lactation did not induce any change in total amino acid availability (expressed per 100 g body wt.). Virgin rats showed a nil hepatic balance, and lactation induced a high net uptake. The high drainage of amino acids by mammary gland does not affect hepatic availability.
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Project description:Under basal conditions (zero insulin), paraovarian adipocytes from 19-day-pregnant rats exhibited the same rates of [U-14C]glucose conversion into CO2 and total lipids as did those from age-matched virgin rats. The dose-response curves for insulin stimulation of glucose metabolism were similar in both groups: maximal response (+100% over basal values) and high sensitivity (half-maximal effect at 0.05 nM-insulin). The present results suggest that the insulin resistance in vivo that occurs during late pregnancy may involve circulating factors lost in vitro.
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Project description:Through a series of epidemiological analyses, flux analyses, and genetic interventions, we identified amino acid as a primary carbon source in hepatic de novo lipogenesis (DNL), and revealed the vital role of dietary protein in non-alcoholic fatty liver disease (NAFLD). To evaluate whether this finding can be applied to treat hepatic steatosis, we implemented protein restriction in obese mice. A short-term low-protein diet (5% kcal protein intake) not only reduced food intake and body weight gain of mice but also ameliorated hepatic lipid accumulation and liver damage. Here, we conducted RNA sequencing for liver samples from these mice and demonstrated a global downregulation of lipogenic genes. Together, this study uncovers a significant role of amino acids in hepatic DNL, and suggests a previously unappreciated target for NAFLD.
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Project description:Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%.The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease.
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Project description:During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by producing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is accompanied by transient hepatic accumulation of glycerolipids. We found that the hepatic expression of monoacylglycerol acyltransferase 1 (Mogat1), an enzyme with monoacylglycerol acyltransferase (MGAT) activity that produces diacyl-glycerol from monoacylglycerol, was significantly increased in the liver of fasted mice compared with mice given ad libitum access to food. Basal and fasting-induced expression of Mogat1 was markedly diminished in the liver of mice lacking the transcription factor PPAR?. Suppressing Mogat1 expression in liver and adipose tissue with antisense oligonucleotides (ASOs) reduced hepatic MGAT activity and triglyceride content compared with fasted controls. Surprisingly, the expression of many other PPAR? target genes and PPAR? activity was also decreased in mice given Mogat1 ASOs. When mice treated with control or Mogat1 ASOs were gavaged with the PPAR? ligand, WY-14643, and then fasted for 18 h, WY-14643 administration reversed the effects of Mogat1 ASOs on PPAR? target gene expression and liver triglyceride content. In conclusion, Mogat1 is a fasting-induced PPAR? target gene that may feed forward to regulate liver PPAR? activity during food deprivation.
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Project description:During the transition between late gestation and early lactation, dairy cows experience severe metabolic stress due to the high energy and nutrient requirements of the fetus and the mammary gland. Additional thermal stress that occurs with rising temperatures during the ongoing climate change has further adverse implications on energy intake, metabolism and welfare. The thyroid hormone (TH)-mediated cellular signaling has a pivotal role in regulation of body temperature, energy intake and metabolic adaptation to heat. To distinguish between energy intake and heat stress-related effects, Holstein cows were first kept at thermoneutrality at 15°C followed by exposure to heat stress (HS) at 28°C or pair-feeding (PF) at 15°C for 6 days, in late pregnancy and again in early lactation. Herein, we focused on hepatic metabolic changes associated with alterations in the hypothalamic-pituitary-thyroid axis in HS and PF animals. T3 and T4 levels dropped with HS or PF; however, in HS animals, this decline was more pronounced. Thyroid-stimulating hormone (TSH) levels remain unaffected, while plasma cholesterol concentrations were lower in HS than PF animals. Hepatic marker genes for TH action (THRA, DIO1 and PPARGC1) decreased after HS and were lower compared to PF cows but only post-partum. Proteomics data revealed reduced hepatic amino acid catabolism ante-partum and a shift toward activated beta-oxidation and gluconeogenesis but declined oxidative stress defense post-partum. Thus, liver metabolism of HS and PF cows adapts differently to diminished energy intake both ante-partum and post-partum, and a different TH sensitivity is involved in the regulation of catabolic processes.
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Project description:Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased (P < 0.05), and threonine was decreased (P < 0.05). In the AA group, fetal arterial pH (7.365 +/- 0.007 day 0 vs. 7.336 +/- 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 +/- 2.6 vs. 37.8 +/- 3.6%, P < 0.005), and total oxygen content (3.17 +/- 0.17 vs. 2.49 +/- 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 +/- 0.73 vs. 8.09 +/- 0.63 micromol x min(-1) x kg(-1), AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 +/- 0.16 vs. 1.84 +/- 0.24 micromol x min(-1) x kg(-1), P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 +/- 23 vs. 250 +/- 29 micromol x min(-1) x kg(-1), P = 0.06). Rates of leucine incorporation into fetal protein (5.19 +/- 0.97 vs. 5.47 +/- 0.89 micromol x min(-1) x kg(-1), AA vs. C), release from protein breakdown (4.20 +/- 0.95 vs. 4.62 +/- 0.74 micromol x min(-1) x kg(-1)), and protein accretion (1.00 +/- 0.30 vs. 0.85 +/- 0.25 micromol x min(-1) x kg(-1)) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2alpha, and p70(S6K). Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation.
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