Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Sterol regulatory element-binding protein 2 (SREBP2) is considered to be a major regulator to control cholesterol homoeostasis in mammals. However, the role of SREBP2 in teleost remains poorly understand. Here, we explored the molecular characterisation of SREBP2 and identified SREBP2 as a key modulator for 3-hydroxy-3-methylglutaryl-coenzyme A reductase and 7-dehydrocholesterol reductase, which were rate-limiting enzymes of cholesterol biosynthesis. Moreover, dietary palm oil in vivo or palmitic acid (PA) treatment in vitro elevated cholesterol content through triggering SREBP2-mediated cholesterol biosynthesis in large yellow croaker. Furthermore, our results also found that PA-induced activation of SREBP2 was dependent on the stimulating of endoplasmic reticulum stress (ERS) in croaker myocytes and inhibition of ERS by 4-Phenylbutyric acid alleviated PA-induced SREBP2 activation and cholesterol biosynthesis. In summary, our findings reveal a novel insight for understanding the role of SREBP2 in the regulation of cholesterol metabolism in fish and may deepen the link between dietary fatty acid and cholesterol biosynthesis.

Choline plays a crucial role in hepatic lipid homeostasis by acting as a major methyl-group donor. However, despite this well-accepted fact, no study has yet explored how choline’s methyl-donor function contributes to preventing hepatic lipid dysregulation. Moreover, the potential regulatory role of Ire-1α, an ER-transmembrane transducer for the unfolded protein response (UPRer), in choline-mediated hepatic lipid homeostasis remains unexplored. Thus, this study investigated the mechanism by which choline prevents hepatic lipid dysregulation, focusing on its role as a methyl-donor and the involvement of Ire-1α in this process. To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco) were fed two different diets (adequate or deficient choline diets) in vivo for 10 weeks. The key findings of studies are as follows: 1. Dietary choline, upregulated selected lipolytic and fatty acid β-oxidation transcripts promoting hepatic lipid homeostasis. 2. Dietary choline ameliorated UPRer and prevented hepatic lipid dysregulation mainly through ire-1α signalling, not perk or atf-6α signalling. 3. Choline inhibited the transcriptional expression level of ire-1α by activating site-specific DNA methylations in the promoter of ire-1α. 4. Choline-mediated ire-1α methylations reduced Ire-1α/Fas interactions, thereby further inhibiting Fas activity and reducing lipid droplet deposition. These results offer a novel insight into the direct and indirect regulation of choline on lipid metabolism genes and suggests a potential crosstalk between ire-1α signalling and choline-deficiency-induced hepatic lipid dysregulation, highlighting the critical contribution of choline as a methyl-donor in maintaining hepatic lipid homeostasis.

The term ‘autophagy’ literally translates to ‘self-eating’ and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.

In this review, the relevance of selenium (Se) to viral disease will be discussed paying particular attention to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). Se, the active centre in selenoproteins has an ongoing history of reducing the incidence and severity of viral infections. Host Se deficiency increased the virulence of RNA viruses such as influenza A and coxsackievirus B3, the latter of which is implicated in the development of Keshan disease in north-east China. Significant clinical benefits of Se supplementation have been demonstrated in HIV-1, in liver cancer linked to hepatitis B, and in Chinese patients with hantavirus that was successfully treated with oral sodium selenite. China is of particular interest because it has populations that have both the lowest and the highest Se status in the world. We found a significant association between COVID-19 cure rate and background Se status in Chinese cities; the cure rate continued to rise beyond the Se intake required to optimise selenoproteins, suggesting an additional mechanism. Se status was significantly higher in serum samples from surviving than non-surviving COVID-19 patients. As regards mechanism, SARS-CoV-2 may interfere with the human selenoprotein system; selenoproteins are important in scavenging reactive oxygen species, controlling immunity, reducing inflammation, ferroptosis and endoplasmic reticulum (ER) stress. We found that SARS-CoV-2 significantly suppressed mRNA expression of GPX4, of the ER selenoproteins, SELENOF, SELENOM, SELENOK and SELENOS and down-regulated TXNRD3. Based on the available data, both selenoproteins and redox-active Se species (mimicking ebselen, an inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host) could employ their separate mechanisms to attenuate virus-triggered oxidative stress, excessive inflammatory responses and immune-system dysfunction, thus improving the outcome of SARS-CoV-2 infection.

Dietary l-carnitine (LC) is a nutritional factor that reduces liver lipid content. However, whether dietary LC can improve lipid metabolism via simultaneous activation of mitochondrial fatty acid (FA) β-oxidation and suppression of endoplasmic reticulum (ER) stress is still unknown. Large yellow croaker were fed with a high-fat diet (HFD) supplemented with dietary LC at 0, 1·2 or 2·4 ‰ for 10 weeks. The results indicated that a HFD supplemented with LC reduced the liver total lipid and TAG content and improved serum lipid profiles. LC supplementation administered to this fish increased the liver antioxidant capacity by decreasing serum and liver malondialdehyde levels and enhancing the liver antioxidant capacity, which then relieved the liver damage. Dietary LC increased the ATP dynamic process and mitochondrial number, decreased mitochondrial DNA damage and enhanced the protein expression of mitochondrial β-oxidation, biogenesis and mitophagy. Furthermore, dietary LC supplementation increased the expression of genes and proteins related to peroxisomal β-oxidation and biogenesis. Interestingly, feeding fish with LC-enriched diets decreased the protein levels indicative of ER stress, such as glucose-regulated protein 78, p-eukaryotic translational initiation factor 2a and activating transcription factor 6. Dietary LC supplementation downregulated mRNA expression relative to FA synthesis, reduced liver lipid and relieved liver damage through regulating β-oxidation and biogenesis of mitochondria and peroxisomes, as well as the ER stress pathway in fish fed with HFD. The present study provides the first evidence that dietary LC can improve lipid metabolism via simultaneously promoting FA β-oxidation capability and suppressing the ER stress pathway in fish.

This study assessed the molecular mechanism of EPA or DHA protection against intestinal porcine epithelial cell line 1 (IPEC-1) cell damage induced by deoxynivalenol (DON). The cells were divided into six groups, including the CON group, the EPA group, the DHA group, the DON group, the EPA + DON group and the DHA + DON group. RNA sequencing was used to investigate the potential mechanism, and qRT-PCR was employed to verify the expression of selected genes. Changes in ultrastructure were used to estimate pathological changes and endoplasmic reticulum (ER) injury in IPEC-1 cells. Transferrin receptor 1 (TFR1) was tested by ELISA. Fe2+ and malondialdehyde (MDA) contents were estimated by spectrophotometry, and reactive oxygen species (ROS) was assayed by fluorospectrophotometry. RNA sequencing analysis showed that EPA and DHA had a significant effect on the expression of genes involved in ER stress and iron balance during DON-induced cell injury. The results showed that DON increased ER damage, the content of MDA and ROS, the ratio of X-box binding protein 1s (XBP-1s)/X-box binding protein 1u (XBP-1u), the concentration of Fe2+ and the activity of TFR1. However, the results also showed that EPA and DHA decreased the ratio of XBP-1s/XBP-1u to relieve DON-induced ER damage of IPEC-1 cells. Moreover, EPA and DHA (especially DHA) reversed the factors related to iron balance. It can be concluded that EPA and DHA reversed IPEC-1 cell damage induced by DON. DHA has the potential to protect IPEC-1 cells from DON-induced iron imbalance by inhibiting ER stress.

The study was conducted to determine the effects of three dietary Se sources, such as sodium-selenite (S-S), seleno-yeast (S-Y) and seleno-methionine (S-M), on Se concentration, glutathione peroxidase (GPX) and TXNRD activities, and mRNA expression of fifteen representative selenoproteins, and protein expression of four endoplasmic reticulum-resided selenoproteins in a wide range of tissues of yellow catfish. Compared with S-S and S-M groups, dietary S-Y significantly decreased growth performance and feed utilisation of yellow catfish. Dietary Se sources significantly influenced Se contents in the spleen, dorsal muscle and the kidney, GPX activities in spleen, kidney, intestine, muscle and mesenteric fat, and TXNRD activities in the heart, intestine and mesenteric fat. Among ten tested tissues, dietary Se sources influenced mRNA expression of GPX4 and SELENOK in three tissues; GPX3, SELENOS and TXNRD2 in four tissues; SELENOF, SELENON and DIO2 in five tissues; SELENOM, GPX1/2 and TXNRD3 in six tissues; SELENOW in seven tissue and SELENOP and SELENOT in eight tissues. Based on these observations above, S-S and S-M seem to be suitable Se sources for improving growth performance and feed utilisation of yellow catfish. Dietary Se sources differentially influence the expression of selenoproteins in various tissues of yellow catfish. For the first time, we determined the expression of selenoproteins in fish in responses to dietary Se sources, which contributes to a better understanding of the functions and regulatory mechanisms of selenoporteins.

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, insulin resistance (IR) and dyslipidaemia. Consumption of a high-fat diet (HFD) enriched in SFA leads to the accumulation of ceramide (Cer), the central molecule in sphingolipid metabolism. Elevations in plasma and tissue Cer are found in obese individuals, and there is evidence to suggest that Cer lipotoxicity contributes to the MetS. EPA and DHA have shown to improve MetS parameters including IR, inflammation and hypertriacylglycerolaemia; however, whether these improvements are related to Cer is currently unknown. This review examines the potential of EPA and DHA to improve Cer lipotoxicity and MetS parameters including IR, inflammation and dyslipidaemia in vitro and in vivo. Current evidence from cell culture and animal studies indicates that EPA and DHA attenuate palmitate- or HFD-induced Cer lipotoxicity and IR, whereas evidence in humans is greatly lacking. Overall, there is intriguing potential for EPA and DHA to improve Cer lipotoxicity and related MetS parameters, but more research is warranted.

Se is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to coronavirus disease 2019 (COVID-19). Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.

The present study compared the protective effect of sodium selenite (SS) and selenomethionine (SeMet) on heat stress (HS)-invoked porcine IPEC-J2 cellular damage and integrate potential roles of corresponding selenoprotein. Cells were cultured at 37°C until 80 % confluence and then subjected to four different conditions for 24 h: at 37°C (control), 41·5°C (HS), 41·5°C supplied with 0·42 µmol Se/L SS (SS), or SeMet (SeMet). HS significantly decreased cell viability, up-regulated mRNA and protein levels of heat shock protein 70 (HSP70) and down-regulated mRNA and protein levels of tight junction-related proteins (claudin-1 (CLDN-1) and zonula occludens-1 (ZO-1)). HS-induced cell injury was associated with the up-regulation (P < 0·05) of six inflammation-related genes and fourteen selenoprotein encoding genes and down-regulation (P < 0·05) of two inflammation-related genes and five selenoprotein encoding genes. Compared with the HS group, SS and SeMet supplementation resulted in an increase (P < 0·05) in cell viability, decreased (P < 0·05) mRNA expression of HSP70 and six inflammation-related genes and rescue (P < 0·05) of mRNA and protein levels of CLDN-1 and ZO-1. SS and SeMet supplementation changes the expressions of nineteen selenoprotein encoding genes in cells affected by HS. Both Se supplementation significantly recovered the protein level of glutathione peroxidase-1 and increased selenoprotein P in the IPEC-J2 cells under HS, respectively. In summary, Se supplementation alleviated the negative impact of HS on IPEC-J2 cells, and their cellular protective effect was associated with regulation expression of selenoproteins, and SeMet exhibited a better protective effect.

While strong evidence from clinical studies suggests beneficial effects of carnitine supplementation on metabolic health, serious safety concerns associated with carnitine supplementation have been raised from studies in mice. Considering that the carnitine doses in these mice studies were up to 100 times higher than those used in clinical studies, the present study aimed to address possible safety concerns associated with long-term supplementation of a carnitine dose used in clinical trials. Two groups of NMRI mice were fed either a control or a carnitine-supplemented diet (1 g/kg diet) from weaning to 19 months of age, and parameters of hepatic lipid metabolism and stress signalling and skeletal muscle gene expression were analysed in the mice at 19 months of age. Concentrations of free carnitine and acetylcarnitine in plasma and tissues were higher in the carnitine than in the control group (P<0·05). Plasma concentrations of free carnitine and acetylcarnitine were higher in mice at adult age (10 and 15 months) than at advanced age (19 months) (P<0·05). Hepatic mRNA and protein levels of genes involved in lipid metabolism and stress signalling and hepatic and plasma lipid concentrations did not differ between the carnitine and the control group. Skeletal muscle transcriptome analysis in 19-month-old mice revealed only a moderate regulation between carnitine and control group. Lifelong carnitine supplementation prevents an age-dependent impairment of plasma carnitine status, but safety concerns associated with long-term supplementation of carnitine at doses used in clinical trials can be considered as unfounded.

TorsinA is a member of the AAA+ superfamily of adenosine triphosphatases. These AAA+ proteins have numerous biological functions, including vesicle fusion, cytoskeleton dynamics, intracellular trafficking, protein folding, and degradation as well as organelle biogenesis. Of particular interest is torsinA, which is mainly located in the endoplasmic reticulum (ER) and nuclear envelope (NE). Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1 dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1. A bioinformatics study of the torsinA interactome revealed reproductive processes to be highly relevant, as proteins in this class were found to interact with the former. Interestingly, the torsin protein family had never been previously described to be associated with the mammalian spermatogenic process. Histological staining of torsinA in human testis tissue revealed a granular cytoplasmic localization in mid- and late spermatocytes. We further sought to understand this newly discovered expression of torsinA in the meiotic phase of human spermatogenesis by studying its specific subcellular distribution. TorsinA is not present in the ER as commonly described. The proposal that torsinA might relocate to the pro-acrosomal vesicles in the Golgi apparatus is discussed.

Dietary phosphoglycerides and n-3 long-chain PUFA (LC-PUFA) play important functions in the development of pikeperch (Sander lucioperca) larvae. This study aimed to determine optimal dietary levels of soyabean lecithin (SBL)-derived phospholipids (PL) in starter feeds for pikeperch larvae 10–30 d post-hatch (DPH) and examine performance and ontogeny by additional supplementation of n-3 LC-PUFA in the form of Algatrium DHA 70 (glyceride product; 660–700 mg/g DHA; EPA 60–75 mg/g). In total, six isoproteic and isoenergetic extruded diets were formulated with increasing levels of PL (3·7, 8·3 or 14·5 % wet weight (w.w.), respectively); however, three of the diets were supplemented with three levels of Algatrium DHA 70 (0·6, 2·0 or 3·4 %, respectively). Liver proteomic analyses of larvae at 30 DPH were included for effects of PL and primarily DHA on performance, physiological expression and interactions in larval proteins. In addition, bone anomalies, digestive enzymatic activity, candidate gene expression and skeleton morphogenesis were examined. Results confirmed the importance of dietary PL levels of at least 8·2 % w.w., and an additional beneficiary effect of supplementation with DHA plus EPA. Thus, combined supplementation of SBL (up to 14·51 % w.w. PL) and n-3 LC-PUFA (1·004 % DM DHA and 0·169 % DM EPA) in the form of TAG resulted in highest growth and lowest incidence of anomalies, improved digestive enzyme activity and had differential effect on liver proteomics. The results denote that essential fatty acids can be supplemented as TAG to have beneficial effects in pikeperch larvae development.

Long-term control of leafy spurge with glyphosate requires multiple applications because the plant reproduces vegetatively from abundant underground adventitious buds, referred to as crown and root buds. Determining the molecular mechanisms involved in controlling vegetative reproduction in leafy spurge following foliar glyphosate treatment could identify limiting factors or new targets for manipulation of plant growth and development in invasive perennial species. Thus, we treated leafy spurge plants with 0 or 2.24 kg ai ha−1 glyphosate to determine its impact on selected molecular processes in crown buds derived from intact plants and plants decapitated at the soil surface 7 d after glyphosate treatment. New shoot growth from crown buds of foliar glyphosate-treated plants was significantly reduced compared with controls after growth-inducing decapitation, and had a stunted or bushy phenotype. Quantification of a selected set of transcripts involved in hormone biosynthesis and signaling pathways indicated that glyphosate had the most significant impact on abundance of ENT-COPALYL DIPHOSPHATE SYNTHETASE 1, which is involved in a committed step for gibberellin biosynthesis, and auxin transporters including PINs, PIN-LIKES, and ABC TRANSPORTERS. Foliar glyphosate treatment also reduced the abundance of transcripts involved in cell cycle processes, which would be consistent with altered growth patterns observed in this study. Overall, these results suggest that interplay among phytohormones such as auxin, ethylene, and gibberellins affect vegetative growth patterns from crown buds of leafy spurge in response to foliar glyphosate treatment.

Retrograde transport is a process in which proteins are trafficked from the plasma membrane and endosomes to biosynthetic and secretory organelles, namely the Golgi apparatus and endoplasmic reticulum (ER). A number of plant and bacterial toxins, including cholera toxin and ricin toxin, exploit retrograde transport to gain entry into host cells, although the specifics of this process have remained difficult to probe by laser scanning confocal microscopy (LSCM). Here we demonstrate the use of super-resolution and live-cell imaging [stimulated emission depletion (STED)] to visualize exogenously applied ricin toxin within the ER. The improved resolution obtained by STED, as compared with LSCM (0.09 versus 0.19 μm), provides a more accurate determination of the amount of ricin that had trafficked to the ER.

The endothelium, a thin single sheet of endothelial cells, is a metabolically active layer that coats the inner surface of blood vessels and acts as an interface between the circulating blood and the vessel wall. The endothelium through the secretion of vasodilators and vasoconstrictors serves as a critical mediator of vascular homeostasis. During the development of the vascular system, it regulates cellular adhesion and vessel wall inflammation in addition to maintaining vasculogenesis and angiogenesis. A shift in the functions of the endothelium towards vasoconstriction, proinflammatory and prothrombic states characterise improper functioning of these cells, leading to endothelial dysfunction (ED), implicated in the pathogenesis of many diseases including diabetes. Major mechanisms of ED include the down-regulation of endothelial nitric oxide synthase levels, differential expression of vascular endothelial growth factor, endoplasmic reticulum stress, inflammatory pathways and oxidative stress. ED tends to be the initial event in macrovascular complications such as coronary artery disease, peripheral arterial disease, stroke and microvascular complications such as nephropathy, neuropathy and retinopathy. Numerous strategies have been developed to protect endothelial cells against various stimuli, of which the role of polyphenolic compounds in modulating the differentially regulated pathways and thus maintaining vascular homeostasis has been proven to be beneficial. This review addresses the factors stimulating ED in diabetes and the molecular mechanisms of natural polyphenol antioxidants in maintaining vascular homeostasis.

High-producing dairy cows enter a period of negative energy balance during the first weeks of lactation. Energy intake is usually sufficient to cover the increase in energy requirements for fetal growth during the period before calving, but meeting the demand for energy is often difficult during the early stages of lactation. A catabolic state predominates during the transition period, leading to the mobilisation of energy reserves (NEFA and amino acids) that are utilised mainly by the liver and muscle. Increased uptake of mobilised NEFA by the liver, combined with the limited capacity of hepatocytes to either oxidise fatty acids for energy or to incorporate esterified fatty acids into VLDL results in fatty liver syndrome and ketosis. This metabolic disturbance can affect the general health, and it causes economic losses. Different nutritional strategies have been used to restrict negative effects associated with the energy challenge in transition cows. The provision of choline in the form of rumen-protected choline (RPC) can potentially improve liver function by increasing VLDL exportation from the liver. RPC increases gene expression of microsomal TAG transfer protein and APOB100 that are required for VLDL synthesis and secretion. Studies with RPC have looked at gene expression, metabolic hormones, metabolite profiles, milk production and postpartum reproduction. A reduction in liver fat and enhanced milk production has been observed with RPC supplementation. However, the effects of RPC on health and reproduction are equivocal, which could reflect the lack of sufficient dose–response studies.

Initial successful weight loss is often followed by weight regain after the dietary intervention. Compared with lean people, cellular stress in adipose tissue is increased in obese subjects. However, the relation between cellular stress and the risk for weight regain after weight loss is unclear. Therefore, we determined the expression levels of stress proteins during weight loss and weight maintenance in relation to weight regain. In vivo findings were compared with results from in vitro cultured human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. In total, eighteen healthy subjects underwent an 8-week diet programme with a 10-month follow-up. Participants were categorised as weight maintainers or weight regainers (WR) depending on their weight changes during the intervention. Abdominal subcutaneous adipose tissue biopsies were obtained before and after the diet and after the follow-up. In vitro differentiated SGBS adipocytes were starved for 96 h with low (0·55 mm) glucose. Levels of stress proteins were determined by Western blotting. WR showed increased expressions of β-actin, calnexin, heat shock protein (HSP) 27, HSP60 and HSP70. Changes of β-actin, HSP27 and HSP70 are linked to HSP60, a proposed key factor in weight regain after weight loss. SGBS adipocytes showed increased levels of β-actin and HSP60 after 96 h of glucose restriction. The increased level of cellular stress proteins in the adipose tissue of WR probably resides in the adipocytes as shown by in vitro experiments. Cellular stress accumulated in adipose tissue during weight loss may be a risk factor for weight regain.

Previously we have examined the effects of diets deficient in folic acid ( − F) or folate deficient with low methionine and choline ( − F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the − F diet. When dams were fed the − F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the − F LM LC group but not in the − F group. Metabolic enzymes associated with lipid metabolism changed in both the − F and − F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the − F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the − F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARα and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.