Altered Liver Metabolism, Mitochondrial Function, Oxidative Status, and Inflammatory Response in Intrauterine Growth Restriction Piglets with Different Growth Patterns before Weaning

Abstract

Frequent occurrence of intrauterine growth restriction (IUGR) causes huge economic losses in the pig industry. Accelerated catch-up growth (CUG) in the early stage of life could restore multiple adverse outcomes of IUGR offspring; however, there is little knowledge about this beneficial phenomenon. We previously found that nutrient absorption related to intestinal function was globally promoted in CUG-IUGR piglets before weaning, which might be the dominant reason for CUG, but what this alteration could lead to in subsequent liver metabolism is still unknown. Firstly, a Normal, CUG, and non-catch-up growth (NCUG) piglet model before weaning was established by dividing eighty litters of newborn piglets into normal birth weight (NBW) and IUGR groups according to birth weight, and those piglets with IUGR but above-average weanling body weight were considered CUG, and the piglets with IUGR still below average body weight were considered NCUG at weaning day (d 26). Liver samples were collected and then systematically compared in glycolipid metabolism, mitochondrial function, antioxidant status, and inflammatory status among these three different growth models. Enhanced hepatic uptake of fatty acids, diminished de novo synthesis of fatty acids, and increased oxidation of fatty acids were observed in CUG livers compared to Normal and NCUG. In contrast, the NCUG liver showed enhanced glucose uptake and gluconeogenesis compared to Normal and CUG. We also observed deteriorating hepatic vacuolation in NCUG piglets, while increasing hepatic lipid deposition in CUG piglets. Besides, the expression of genes related to mitochondrial energy metabolism and biogenesis was reduced in CUG piglets and the phosphorylation level of AMPK was significantly higher compared to Normal (p < 0.05). Moreover, NCUG liver showed decreased T-AOC (p < 0.01) and GSH-PX (p < 0.05), increased MDA concentrations (p < 0.01), upregulated phosphorylation levels of ERK and NF-κB (p < 0.05), and elevated pro-inflammatory factors IL-1β, IL-6 and TNF-α (p < 0.05) compared to Normal. Furthermore, correlation analysis revealed a significant positive correlation between glucose metabolism and inflammatory factors, while a negative correlation between mitochondrial function-related genes and fatty acid transport. NGUG piglets showed simultaneous enhancement of glucose uptake and gluconeogenesis, as well as reduced antioxidant capacity and increased inflammatory status, whereas CUG comes at the expense of impaired hepatic mitochondrial function and pathological fat accumulation.

Unraveling hepatic consequences of intrauterine growth restriction and catch- up growth: Insights from histological, biochemical, and metabolomic analysis in rats Running title: Hepatic Metabolomics and Intrauterine Growth Retardation

“…Studies have consistently reported increased oxidative stress in both the serum and the livers of newborns affected by IUGR [19,20,22,23]. This heightened hepatic oxidative stress is often attributed to an imbalance between the accumulation of free radicals and the production of antioxidant enzymes [21,24].…”

Dousing the flame: reviewing the mechanisms of inflammatory programming during stress-induced intrauterine growth restriction and the potential for ω-3 polyunsaturated fatty acid intervention

“…In IUGR fetal guinea pigs, hepatic utilization of palmitate (the most common saturated fatty acid in animals and plants) was reduced by about 50% ( Detmer et al, 1992 ). Conversely, IUGR-born neonatal goats had greater liver accumulation of NEFA, triglycerides, and cholesterol ( Liu et al, 2022 ), and IUGR-born runt piglets had more expansive hepatic lipid droplets, particularly after undergoing catch-up growth ( Wang et al, 2022 ). IUGR-induced changes in lipid metabolism were largely tissue-specific, as were changes in de novo synthesis.…”

“…Shortly after birth, IUGR infants exhibited greater rates of whole-body triglyceride mobilization and fatty acid oxidation ( Patel and Kalhan, 1992 ). Moreover, gene expression for the key β-oxidation facilitator PPARα was increased in liver tissue from IUGR-born runt piglets ( Wang et al, 2022 ) and in cardiac muscle from IUGR-born adult guinea pigs ( Botting et al, 2018 ). Gene expression for CPT1 and HADHA, which play rate-limiting roles for fatty acid β-oxidation, was reduced in liver tissues of IUGR-born rats ( Lane et al, 2001a ).…”

“… Stress-induced programming of enriched inflammatory signaling pathways in IUGR sheep tissues. Findings compiled from the literature are shown for skeletal muscle ( Llovera et al, 1997 ; Bodell et al, 2009 ; Gray et al, 2009 ; Cadaret et al, 2017 ; Cadaret et al, 2019c ; Hicks and Yates, 2021 ; Posont et al, 2022 ), liver ( Fitzgerald et al, 2003 ; Zarate et al, 2021 ; Zhang et al, 2021 ; Wang et al, 2022 ), pancreas ( Hadjivassiliou et al, 1998 ; Andersson et al, 2005 ; Ellingsgaard et al, 2011 ; Kelly et al, 2017 ), and adipose tissue ( Kras et al, 2000 ; Sharkey et al, 2009 ; Beer, 2022 ). Green boxes indicate signaling components reported to be upregulated and red boxes indicate downregulated components.…”