PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition

doi:10.1016/j.bbalip.2019.158548

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1865, Issue 2, February 2020, 158548

https://doi.org/10.1016/j.bbalip.2019.158548 Get rights and content

Highlights

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Lipid metabolism disorder in maternal liver is related to PPARA/RXRA signalling.
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NEFAs activate PPARA signalling, enhance FAO, and reduce lipogenesis.
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BHBA inhibits RXRA signalling, represses FAO, and increases lipogenesis.
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Activating PPARA/RXRA signalling optimizes the homeostasis of lipid metabolism.

Abstract

Maternal undernutrition during late gestation accelerates body fat mobilization to provide more energy for foetal growth and development, which unbalances metabolic homeostasis and results in serious lipid metabolism disorder. However, detailed regulatory mechanisms are poorly understood. Here, a sheep model was used to explore the regulatory role of PPARA/RXRA signalling in hepatic lipid metabolism in undernutrition based on RNA sequencing and cell experiments. KOG function classification showed that lipid transport and metabolism was markedly altered in an undernourished model. In detail, when compared with the controls, fatty acid transport and oxidation and triglyceride metabolism were up-regulated in an undernourished model, while fatty acid synthesis, steroid synthesis, and phospholipid metabolism were down-regulated. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis demonstrated that PPARA/RXRA signalling pathway was altered. Moreover, PPARA signalling associated genes were positively correlated with hepatic non-esterified fatty acid (NEFA) levels, while retinol metabolism associated genes were negatively correlated with blood beta-hydroxybutyric acid (BHBA) levels. Results of primary hepatocytes showed that NEFAs could activate PPARA signalling and facilitate fatty acid oxidation (FAO) and ketogenesis, while BHBA could inhibit RXRA signalling and repress FAO and ketogenesis. Excessively accumulated NEFAs in hepatocytes promoted triglyceride synthesis. Furthermore, activation of PPARA/RXRA signalling by WY14643 and 9-cis-retinoic acid could enhance FAO and ketogenesis and reduce NEFAs accumulation and esterification. Our findings elucidate the regulatory mechanisms of NEFAs and BHBA on lipid metabolism as well as the potential role of the PPARA/RXRA signalling pathway in hepatic lipid metabolism, which may contribute to exploring new strategies to maintain lipid metabolic homeostasis in human beings.

Graphical abstract

Introduction

During late gestation, much more additional energy is required to support foetal growth and development, so negative energy balance is a prevalent physiological characteristic for pregnant mothers. Maternal undernutrition before or during gestation increases the risk of the mother developing metabolic disorders and complications [1]. Moreover, the mother's nutritional status is responsible for the child's health [2], and maternal undernutrition is a prime cause of children's morbidity and mortality. Mothers carrying multiple foetuses require much more energy and are more susceptible to undernutrition. Under this condition, body fat mobilization is facilitated to generate non-esterified fatty acids (NEFAs) for oxidation to provide more ATP. In the liver, NEFAs can be converted to acetyl-CoA through fatty acid oxidation (FAO) and then completely oxidized to CO₂ and H₂O or incompletely metabolized to beta-hydroxybutyric acid (BHBA) or cholesterol. NEFAs can also be esterified into triglycerides, which results in triglyceride accumulation in the liver, leading to impaired liver function. Promoting FAO to generate more ATP and reduce triglyceride synthesis is critical for the survival of mother and baby.

From the perspective of nutrigenomics, nutrients are dietary signals that can be investigated by cellular sensor systems and influence the expression of genes and subsequent metabolite production [3]. Some previous findings showed that peroxisome proliferator-activated receptor (PPAR) alpha (PPARA) signalling regulates the expression of genes associated with fatty acid metabolism [[4], [5], [6]]. In addition, ketogenesis is controlled by associated genes, especially the rate-limiting enzyme gene beta-hydroxy-beta-methylglutaryl-CoA synthase 2 (HMGCS2) [7,8] which is also regulated by the PPARA signalling pathway [4,6]. Meanwhile, Li et al. [9] reported that BHBA inhibited both gene and protein expression of HMGCS2 in bovine hepatocytes. However, it is not clear whether PPARA signalling is adjusted by NEFAs or BHBA and whether the activation of PPARA signalling can be used to relieve lipid metabolism disorder in the liver of undernourished pregnant mothers.

Many animal models have been developed to examine potential mechanisms that drive these physiological changes to provide new insights into the epidemiological findings. As the most commonly used animal model, mice are ethically accepted and easy to handle and manage. Mice also reproduce rapidly, provide low cost, and allow for genetic modifications. However, mice model also has limitations, such as small body size, short gestational period (18–21 days), and large number of embryos per litter, which are very different from the pregnancy features of human beings. These disadvantages also make it difficult to implement long-term sampling and in vivo imaging [10]. In contrast, sheep are human-sized animals with a relatively long gestation (145–154 days) and small number of embryos per litter (mainly singleton or twin), which makes their pregnancy more similar to human pregnancy. Moreover, pregnant sheep are tolerant to invasive procedures and easy to handle, and lamb weight is about the same as a human foetus [10,11]. Considering these advantages, sheep make an excellent model and have been used to research human pregnancy and the metabolic mechanisms of mother–child nutrition [12,13].

In this study, an undernourished pregnancy model was developed in sheep to test the hypothesis that substrate NEFAs and product BHBA could regulate the PPARA signalling pathway, and in turn, the activation of the PPARA signalling might change the fate of NEFAs to increase the energy supply. We show that lipid transport and metabolism was markedly altered in this undernourished pregnancy model, and the PPARA/retinoid X receptor alpha (RXRA) signalling pathway was enriched by differentially expressed genes (DEGs). We found that PPARA signalling and retinol metabolism associated genes were significantly correlated with the levels of hepatic NEFAs and BHBA, respectively. We demonstrate the regulatory role of the PPARA/RXRA signalling pathway in lipid metabolism in cultured Ovis aries hepatocytes. The novelty of the current study is that BHBA can inhibit RXRA signalling and negatively regulate FAO and ketogenesis, further, the activation of PPARA/RXRA signalling increases NEFAs metabolism and decreases NEFAs esterification in the liver. This is helpful for finding novel approaches to improve lipid metabolism homeostasis, increase energy supply, and prevent hepatic steatosis.

Section snippets

Animal model and sample collection

The animal model was developed in Yonghui Sheep Industry Co., Ltd. in Shanghai, China. The animal experimental procedures were supported by the Animal Care and Use Committee of Nanjing Agricultural University (SYXK(Su)2015-0656). This study was part of a large project designed to study the effect of undernutrition during late gestation on maternal and foetal metabolism [14]. In brief, twenty purebred sheep carrying 2–4 foetuses and gestating for 108 days, with similar body weight and body

Biochemical indicators in blood and liver

As reported in our previous findings [21], feed restriction increased blood NEFA levels (P < 0.001) and BHBA levels (P < 0.001), and decreased blood glucose levels (P < 0.001). Moreover, hepatic NEFA levels (P < 0.001) and BHBA levels (P < 0.001) in the TR group were higher than in the CON group, respectively. Hematoxylin & eosin staining sections of hepatic tissues showed a number of fat vacuoles stacked in and out of hepatocytes of feed-restricted ewes, which indicated an excessive

Discussion

According to the recommendation by Institute of Medicine, an estimated additional 0, 340, and 452 kcal are required for pregnant women at the first, second, and third trimester, respectively [25]. Insufficient energy and nutrient intake during pregnancy leading to severe maternal outcomes has been widely recognized in observational studies [1]. In order to produce more energy for foetal growth and development, the pregnant mother's body fat is mobilized to increase lipid-derived energy, which

Conclusion

Our findings reveal that negative energy balance induces severe lipid metabolism disorder in the livers of pregnant ewes, which leads to the significant accumulation of NEFAs and BHBA in the liver and blood. NEFAs activate PPARA signalling and promote FAO and ketogenesis, while BHBA inhibits RXRA signalling and restrains FAO and ketogenesis in hepatocytes of sheep. Activation of the PPARA/RXRA signalling pathway by WY and RA in hepatocytes can enhance FAO and ketogenesis and inhibit

Financial support

The current study was supported by National Key Research and Development Program of China (grant number 2016YFD0501200).

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgements

We are grateful to Hongwei Li, Zheng Zhang, Xun Pei, Shijun Mei, Hongbo Zeng, and Wangpan Qi (Nanjing Agricultural University) for taking part in animal and cell experiments. We thank Dr. Xinwei Li and Xiliang Du (Jilin University) for technical assistance on primary hepatocyte isolation and culture. We also thank Biomarker Biotechnology Co., Ltd. (Beijing, China) for technical assistance on RNA sequencing.

References (49)

H.A. Nguyen
Undernutrition during pregnancy
K. Clinkenbeard et al.
Intracellular localization of the 3-hydroxy-3-methylglutaryl coenzme A cycle enzymes in liver. Separate cytoplasmic and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A generating systems for cholesterogenesis and ketogenesis
J. Biol. Chem.
(1975)
O. Morel et al.
The use of ruminant models in biomedical perinatal research
Theriogenology
(2012)
P. Chomczynski et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Anal. Biochem.
(1987)
K.J. Livak et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method
Methods
(2001)
Z.G. Zhang et al.
An updated method for the isolation and culture of primary calf hepatocytes
Vet. J.
(2012)
S.J. Bertics et al.
Effect of prepartum dry matter intake on liver triglyceride concentration and early lactation
J. Dairy Sci.
(1992)
Y. Xue et al.
Molecular mechanisms of lipid metabolism disorder in livers of ewes with pregnancy toxemia
Animal
(2019)
M. Iwersen et al.
Comparison of 2 electronic cowside tests to detect subclinical ketosis in dairy cows and the influence of the temperature and type of blood sample on the test results
J. Dairy Sci.
(2013)
M.A. Kominiarek et al.
Nutrition recommendations in pregnancy and lactation
Med. Clin. N. Am.
(2016)

H. Dann et al.

Carnitine palmitoyltransferase I in liver of periparturient dairy cows: effects of prepartum intake, postpartum induction of ketosis, and periparturient disorders

J. Dairy Sci.

(2005)

J.K. Drackley et al.

Adaptations of glucose and long-chain fatty acid metabolism in liver of dairy cows during the periparturient period

J. Dairy Sci.

(2001)

J.C. Rodriguez et al.

Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids

J. Biol. Chem.

(1994)

C. Palmer et al.

Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter

J. Biol. Chem.

(1994)

I. Issemann et al.

The retinoid X receptor enhances the function of the peroxisome proliferator activated receptor

Biochimie.

(1993)

Q. Saeed et al.

Maternal depressive symptoms and child nutritional status: a cross-sectional study in socially disadvantaged Pakistani community

J. Child Health Care

(2017)

M. Müller et al.

Nutrigenomics: goals and strategies

Nat. Rev. Genet.

(2003)

J.K. Reddy et al.

Peroxisomal β-oxidation and peroxisome proliferator–activated receptor α: an adaptive metabolic system

Annu. Rev. Nutr.

(2001)

J.K. Reddy

Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis

Am. J. Physiol-Gastr. L.

(2001)

S.R. Pyper et al.

PPARalpha: energy combustion, hypolipidemia, inflammation and cancer

Nucl. Recept. Signal.

(2010)

D. Williamson et al.

Activity and intracellular distribution of enzymes of ketone-body metabolism in rat liver

Biochem. J.

(1968)

P. Li et al.

Effect of β-hydroxybutyrate on expression of 3-hydroxy-3-methylglutaryl-CoA synthase in bovine hepatocytes cultured in vitro

Feed Ind.

(2013)

P. Chavatte-Palmer et al.

Diet before and during pregnancy and offspring health: the importance of animal models and what can be learned from them

Int. J. Env. Res. Pub. He.

(2016)

I.C. McMillen et al.

Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition

Basic Clin. Pharmacol.

(2008)

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PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Animal model and sample collection

Biochemical indicators in blood and liver

Discussion

Conclusion

Financial support

Declaration of competing interest

Acknowledgements

J. Biol. Chem.

Theriogenology

Anal. Biochem.

Methods

Vet. J.

J. Dairy Sci.

Animal

J. Dairy Sci.

Med. Clin. N. Am.

J. Dairy Sci.

J. Dairy Sci.

J. Biol. Chem.

J. Biol. Chem.

Biochimie.

Maternal depressive symptoms and child nutritional status: a cross-sectional study in socially disadvantaged Pakistani community

J. Child Health Care

Nutrigenomics: goals and strategies

Nat. Rev. Genet.

Peroxisomal β-oxidation and peroxisome proliferator–activated receptor α: an adaptive metabolic system

Annu. Rev. Nutr.

Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis

Am. J. Physiol-Gastr. L.

PPARalpha: energy combustion, hypolipidemia, inflammation and cancer

Nucl. Recept. Signal.

Activity and intracellular distribution of enzymes of ketone-body metabolism in rat liver

Biochem. J.

Effect of β-hydroxybutyrate on expression of 3-hydroxy-3-methylglutaryl-CoA synthase in bovine hepatocytes cultured in vitro

Feed Ind.

Diet before and during pregnancy and offspring health: the importance of animal models and what can be learned from them

Int. J. Env. Res. Pub. He.

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Basic Clin. Pharmacol.