Maternal protein restriction induces alterations in hepatic tumor necrosis factor-α/CYP7A1 signaling and disorders regulation of cholesterol metabolism in the adult rat offspring

Abstract

It is well recognized that adverse events in utero impair fetal development and lead to the development of obesity and metabolic syndrome in adulthood. To investigate the mechanisms linking impaired fetal growth to increased cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, we examined the impact of maternal undernutrition on tumor necrosis factor-α (TNF-α)/c-jun N-terminal kinase (JNK) signaling pathway and the cholesterol 7α-hydroxylase (CYP7A1) expression in the livers of the offspring with a protein restriction model. The male offspring with intrauterine growth restriction (IUGR) caused by the isocaloric low-protein diet showed decreased liver weight at birth and augmented circulation and hepatic cholesterol levels at 40 weeks of age. Maternal undernutrition significantly upregulated cytokine TNF-α expression and JNK phospholytion levels in the livers from fetal age to adulthood. Elevated JNK phospholytion could be linked to downregulated hepatocyte nuclear factor-4α and CYP7A1 expression, subsequently led to higher hepatic cholesterol. This work demonstrated that intrauterine malnutrition-induced IUGR might result in intrinsic disorder in hepatic TNF-α/CYP7A1 signaling, and contribute to the development of hypercholesterolemia in later life.

Effects and Interactions of Prenatal Ethanol Exposure, a Post-Weaning High-Fat Diet and Gender on Adult Hypercholesterolemia Occurrence in Offspring Rats

“…For example, serum TCH concentrations are increased in offspring rats with PEE [21]. Similarly, serum TCH concentrations in prenatal food-restricted offspring are also increased, and even hepatic cholesterol accumulation has been found [10, 29]. Some epidemiological investigations have found that the incidence of serum cholesterol disorder is increased in 20-year-old adults with low birth weight and is accompanied by increased serum LDL-C and decreased HDL-C levels [30].…”

“…Because the liver is the largest cholesterol metabolic organ, hepatic cholesterol metabolic disorders can directly cause blood cholesterol disorders and are involved in many types of cerebrovascular diseases. It has been reported that increased blood cholesterol level that both occurs after the birth of offspring, and is caused by an adverse prenatal environment may be related to the changes in hepatic cholesterol metabolism [10, 13, 14]. Therefore, the changes in hepatic cholesterol metabolism in IUGR offspring are worthy of great attention [10, 15].…”

“…Specifically, IUGR could be a potential cause of adult hypertension and chronic kidney disease, and the related potential mechanisms have been studied [4-6]; macrosomia can cause the development of childhood obesity and type 2 diabetes and/or cardiovascular diseases in the later stage of life [7]. Traditionally, the incidence of hypercholesterolemia is mainly related to the postnatal environment [8, 9]; however, studies have demonstrated that IUGR is also an independent risk factor for hypercholesterolemia [10, 11]. …”

Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring

“…Intrauterine growth retardation (IUGR) is defined as a developing baby weighing either 10% of or 2 SD less than the mean body weight of other babies of the same gestational age (5). In recent years, population studies and animal experiments have found that children with IUGR have elevated blood cholesterol levels and are susceptible to metabolic diseases in adulthood (6)(7)(8). These results suggest that hypercholesterolemia and its associated diseases may have intrauterine developmental origins.…”

“…Intrauterine programming refers to a scenario in which an intrauterine fetus is exposed to an adverse environment, leading to fetal organ development and functional changes; these changes can persist after birth (13,14). It has been suggested that the elevation of blood cholesterol levels in the IUGR due to the adverse environment during pregnancy may be related to changes in the expression of cholesterol-related genes in the livers of offspring (6,15). However, an intrauterine programming mechanism for PCE-induced hypercholesterolemia in offspring has not been reported.…”