Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity

Abstract

We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.

Endoplasmic reticulum stress epigenetics is related to adiposity, dyslipidemia, and insulin resistance

“…In agreement with our findings, a transgenerational set of epigenetic modifications (mainly reduced accumulation of methylated histones in Lxra/ Nr1h3 and Ero1-a gene promoters) led to up-regulation of lipogenesis and ER stress pathways in the liver of C57BL/6 mice fed a highfat diet [11]. Additionally, the combination of offspring exposure to maternal obesity and the consumption of an obesogenic diet in mice triggered altered UPR signaling rhythmicity, cellular apoptosis, and hypermethylation of GRP78, a chaperone protein and a master regulator of ER homeostasis [12]. Furthermore, treatment of hepatocytes from high-fat diet obese mice with the specialized proresolving lipid mediator maresin 1 (MaR1) protected cells from lipotoxic and hypoxia-induced endoplasmic reticulum stress via specific miRNA signatures targeting both protein folding and apoptosis [30].…”

“…Besides environmental factors, different epigenetic modifications may regulate ER stress response and consequently disease risks [10]. These included DNA and histone methylation patterns in or near ER stress gene promoters and interconnected downstream signaling molecules [10][11][12]. Also, microRNA (miRNA) expression constitutes a fine-tuning mechanism for optimal ER activity during stress conditions [13,14].…”

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

“…Accordingly, Chop was unchanged at the mRNA level. Atf4 gene expression levels were not correlated with protein levels, suggesting posttranscriptional regulation or possible rhythmical activation of the UPR pathway [22], which deserves further research. Molecular chaperone was involved in folding or maintaining of nascent polypeptides [31].…”

“…e UPR is also associated with maternal programming. Maternal obesity triggers alterations in the UPR signaling pathway in hepatic and pancreatic tissues [21,22]. Uterine artery ligation upregulates Atf6 and p-eIF2 in the adipose tissues of juvenile FGR rats, which contributes to the development of glucose intolerance [23].…”

Progress and challenges in the prevention and control of nonalcoholic fatty liver disease

“…Such hits include IR, hormones secreted from adipose tissue, nutritional factors, gut microbiota, and genetic and epigenetic factors . In addition, accumulating evidence revealed that maternal perinatal obesity and environmental overnutrition predispose offspring to NAFLD in adult life …”