Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet

Zinkhan, Erin K.; Yu, Baifeng; McKnight, Robert A.

doi:10.1177/1933719118811649

Cited by 4 publications

(3 citation statements)

References 35 publications

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“…One such mechanism is miRs, which are small, non-coding RNA molecules that silence target genes through mRNA degradation or repressed protein translation. Numerous miRs have been demonstrated to have aberrant postnatal expression in growth-restricted offspring, leading to cellular stress that precedes impaired function of metabolic organs [ 51 , 86 , 87 , 88 ]. Recent studies found that the translation of p66Shc protein is directly inhibited by miR-203a-3p, leading to the attenuation of liver injury and fibrosis in mice [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver

Oke

Lee

Papp

et al. 2021

IJMS

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The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9-THC-exposed offspring. Collectively, these findings indicate that prenatal Δ9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

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Section: Discussionmentioning

confidence: 99%

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver

Oke

Lee

Papp

et al. 2021

IJMS

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“…These changes are indicative of an induction of cholesterol biosynthesis and inhibition of thyroid hormone metabolism, fatty acid beta oxidation, and apelin liver signaling Bioinformatic analysis of DEPs in the FGR group vs. control showed induction of cholesterol biosynthesis. Regarding cholesterol biosynthesis, metabolomic studies have shown that FGR fetuses have higher concentrations of cholesterol such as VLDL and LDL, lipoproteins, and triglycerides (31). Lipids are vital molecules for life, providing energy for metabolic processes.…”

Section: Discussionmentioning

confidence: 99%

Liver Proteome Profile of Growth Restricted and Appropriately Grown Newborn Wistar Rats Associated With Maternal Undernutrition

et al. 2021

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BackgroundFetal growth restriction (FGR) has been associated with adverse perinatal outcomes and epigenetic modifications that impact gene expression leading to permanent changes of fetal metabolic pathways and thereby influence development of disease in childhood and adult life. In this study, we investigated the result of maternal food restriction on liver protein expression in Wistar male newborn pups.Materials & MethodsTen (n = 10) timed pregnant Wistar rats on their 14th day of gestation were randomly assigned to either control (n = 4) or food restricted group (n = 6). The control group had ad libitum access to food. In the food restricted group, maternal diet was limited in a moderate fashion (50%) from day 15 of pregnancy until delivery. All rats delivered spontaneously on day 21 and newborn pups were immediately weighed. Pups born to normally nourished mothers were considered as controls, while pups born to food restricted mothers were subdivided into two groups, based on their birth weight: growth restricted (FGR) and appropriately grown (non-FGR). Rats were euthanized immediately after birth and liver tissues of 11 randomly selected male offspring (FGR n = 4, non-FGR n = 4, control n = 3) were collected and analyzed using quantitative proteomics.ResultsIn total 6,665 proteins were profiled. Of these, 451 and 751 were differentially expressed in FGR and non-FGR vs. control, respectively, whereas 229 proteins were commonly expressed. Bioinformatics analysis of the differentially expressed proteins (DEPs) in FGR vs. control revealed induction of the super-pathway of cholesterol biosynthesis and inhibition of thyroid hormone metabolism, fatty acid beta oxidation and apelin liver signaling pathway. Analysis of DEPs in non-FGR vs. control groups showed inhibition of thyroid hormone metabolism, fatty acid beta oxidation, and apelin liver signaling pathway.ConclusionThis study demonstrates the impact of prenatal food restriction on the proteomic liver profile of FGR and non-FGR offspring underlying the importance of both prenatal adversities and birth weight on liver-dependent postnatal disease.

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“…One such mechanism is miRs, which are small, non-coding RNA molecules that silence target genes through mRNA degradation or repressed protein translation. Numerous miRs have been demonstrated to have aberrant postnatal expression in growth-restricted offspring, leading to cellular stress that precedes impaired function of metabolic organs [51,[86][87][88]. Recent studies have found that the translation of p66Shc protein is directly inhibited by miR-203a-3p, leading to the attenuation of liver injury and fibrosis in mice [56].…”

Section: Discussionmentioning

confidence: 99%

In Utero Exposure to 9-Tetrahydrocannabinol Leads to Postnatal Catch-up Growth and Dysmetabolism in the Adult Rat Liver

Oke¹,

Lee²,

Papp³

et al. 2021

Preprint

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Rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to 9-tetrahydrocannabinol (9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that 9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg 9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to 9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, 9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACC, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, was also observed in these 9-THC-exposed offspring. Collectively, these findings indicate that prenatal 9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

show abstract

Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet

Cited by 4 publications

References 35 publications

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver

Liver Proteome Profile of Growth Restricted and Appropriately Grown Newborn Wistar Rats Associated With Maternal Undernutrition

In Utero Exposure to 9-Tetrahydrocannabinol Leads to Postnatal Catch-up Growth and Dysmetabolism in the Adult Rat Liver

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