Differential hepatic lobar gene expression in offspring exposed to altered maternal dietary protein intake

Abstract

Increased plasma fibrinogen concentrations are a recognized risk factor for coronary heart disease, and increased fibrinogen levels in adults are associated with parameters of reduced early growth. We studied fibrinogen gene expression in adult offspring of dams fed either a 20% (control) or an 8% protein diet [maternal low-protein (MLP) rats] during pregnancy and lactation and determined whether any effects were consistent between left and right liver lobes, since the fetal liver has a unique blood supply that produces differential stimuli to the left and right lobes. In MLP offspring, there was a reduction in all three fibrinogen mRNA copy numbers in the left liver lobe [left vs. right lobes for alpha-, beta-, and gamma-fibrinogen (x10(6) copies/ng total RNA): 8.04 vs. 23.16, P<0.001; 4.74 vs. 13.07, P<0.001; and 4.61 vs. 16.38, P = 0.007, respectively], with a parallel reduction in fibrinogen concentration in the left liver lobe (8.53+/-0.33 vs. 10.41 +/-0.65 arbitrary units, P = 0.014, left and right lobes, respectively). No such effect was observed in offspring of control dams. To investigate the underlying mechanism, glucocorticoid receptor function and mRNA levels were studied, since expression of fibrinogen genes is regulated by glucocorticoid hormones. The binding affinity of the high-affinity glucocorticoid receptor was reduced only in the left liver lobe of the MLP offspring (P = 0.02, left. vs. right), with a parallel reduction in this lobe in glucocorticoid receptor mRNA level (P = 0.006, left vs. right). In conclusion, maternal dietary protein restriction reduces fibrinogen gene expression, fibrinogen protein, and mRNA level and binding affinity of glucocorticoid receptors only in the left liver lobe of the adult offspring.

A low protein diet during pregnancy provokes a lasting shift of hepatic expression of genes related to cell cycle throughout ontogenesis in a porcine model

“…By means of succeeding direct and indirect interactions of downstream target genes, mRNA expression regarding metabolic, behavioural, cardiovascular and immune functions is modulated. In rodents, many studies reported an impact of maternal low protein diets on expression and affinity of the glucocorticoid receptor and its signaling molecules [8,48,59-61]. Consistently, in porcine offspring a diet-dependent regulation of 'glucocorticoid receptor signaling' was also found.…”

Fetal origins of adult disease: epidemiology and mechanisms

“…Using the same dietary manipulation in the pregnant rat dam as above, we showed that diVerentially reduced fibrinogen gene expression occurred in the left liver lobe compared with the right liver lobe. 41 We suggest that any eVect of maternal nutritional stimuli on development of the fetal liver may also be modulated by the unique fetal liver blood supply. The fetal hepatic circulation is diVerent from that of adults because of the presence of the ductus venosus, which closes shortly after birth in humans (and also in rats and sheep).…”

Sources of variance in baseline gene expression in the rodent liver

“…However, there is evidence of functional heterogeneity among individual liver lobes in the absence or presence of environmental factors. The physiological basis for these differences is likely due to left-right asymmetric portal blood flow during development [63], where fetal left liver lobe receives more nutrients than other regions of the liver [64]. Thus, differences between liver lobes may be programmed during development.…”

“…Thus, differences between liver lobes may be programmed during development. As an example, the adult offspring of Wistar rat dams fed a low protein diet during pregnancy exhibited reduced fibrinogen mRNA and protein levels only in the left lobe of the liver [64]. …”