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Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα - deficient mice (Pparα -/- ) and in mice lacking Pparα only in hepatocytes (Pparα hep-/- ). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.

Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis., Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters., Results: Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers., Conclusion: During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection., Lay Summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and β Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver.

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα(-/-) male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand., Competing Interests: The authors declare no conflicts of interest. The founding sponsors had no role in the design of the study; the collection, analysis, or interpretation of data; writing the manuscript; or the decision to publish the results.

The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenic genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPARα, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPARα axis in which GR directly regulates the transcriptional activation of PPARα by binding to its promoter. Certain PPARα target genes such as Fgf21 remain repressed in the fetal liver and become PPARα responsive after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPARα in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands.

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function.

Since it is associated to the obesity epidemic, non alcoholic fatty liver disease (NAFLD) has become a major public health issue. NAFLD ranges from benign hepatic steatosis, i.e. abnormally elevated triglyceride accumulation, to non alcoholic steatohepatitis (NASH) that can lead to irreversible liver damages. The search for pharmacological and dietary approaches to treat or prevent NAFLD has pointed at nuclear receptors as sensible targets. Indeed, nuclear receptors are ligand-sensitive transcription factors that play a central role in hepatic lipid metabolism. Among nuclear receptors, the liver X receptor has been identified as an oxysterol receptor. It is involved in the control of various aspects of lipid metabolism that are reviewed in this manuscript. We highlight the role of LXR in the gut-liver axis and the studies that have provided a rationale for strategies specifically targeting the hepatic activity of LXR in NAFLD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors belonging to the nuclear hormone receptor family. While PPARs are best known as regulators of energy homeostasis, evidence also has accumulated recently for their involvement in basic cellular functions. We review novel insights into PPAR functions in skin wound healing and liver, with emphasis on PPARβ/δ and PPARα, respectively. Activation of PPARβ/δ expression in response to injury promotes keratinocyte survival, directional sensing, and migration over the wound bed. In addition, interleukin (IL)-1 produced by the keratinocytes activates PPARβ/δ expression in the underlying fibroblasts, which hinders the mitotic activity of keratinocytes via inhibition of IL-1 signaling. Initially, roles were identified for PPARα in fatty acid catabolism. However, PPARα is also involved in downregulating many genes in female mammals. We have elucidated the mechanism of this repression, which requires sumoylation of PPARα. Physiologically, this control confers protection against estrogen-induced intrahepatic cholestasis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes. [ABSTRACT FROM AUTHOR]

Hepatic metabolites provide valuable information on the physiological state of an organism, and thus, they are monitored in many clinical situations. Typically, monitoring requires several analyses for each class of targeted metabolite, which is time consuming. The present study aimed to evaluate a proton nuclear magnetic resonance (1H-NMR) method for obtaining quantitative measurements of aqueous and lipidic metabolites. We optimized the extraction protocol, the standard samples, and the organic solvents for the absolute quantification of lipid species. To validate the method, we analyzed metabolic profiles in livers of mice fed three different diets. We compared our results with values obtained with conventional methods and found strong correlations. The 1H-NMR protocol enabled the absolute quantification of 29 aqueous metabolites and eight lipid classes. Results showed that mice fed a diet enriched in saturated fatty acids had higher levels of triglycerides, cholesterol ester, monounsaturated fatty acids, lactate, 3-hydroxy-butyrate, and alanine and lower levels of glucose, compared to mice fed a control diet. In conclusion, proton NMR provided a rapid overview of the main lipid classes (triglycerides, cholesterol, phospholipids, fatty acids) and the most abundant aqueous metabolites in liver. [ABSTRACT FROM AUTHOR]