Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

Background & Aims: Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear.

Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor.

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice.

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice.

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression.

Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver.

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms.

Hepatic PPARα is critical in the metabolic adaptation to sepsis.

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.

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin.

Nonalcoholic fatty liver disease prevalence is soaring with the obesity pandemic, but the pathogenic mechanisms leading to the progression toward active nonalcoholic steatohepatitis (NASH) and fibrosis, major causes of liver-related death, are poorly defined. To identify key components during the progression toward NASH and fibrosis, we investigated the liver transcriptome in a human cohort of NASH patients. The transition from histologically proven fatty liver to NASH and fibrosis was characterized by gene expression patterns that successively reflected altered functions in metabolism, inflammation, and epithelial-mesenchymal transition.

The logic of transcriptional regulator recruitment architecture at -regulatory modules controlling liver functions.

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at -regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question.

Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression.

Objective: Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH.

Design: We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient () mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control.

Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα Deficiency.

Acute liver failure (ALF) is a severe and rapid liver injury, often occurring without any preexisting liver disease, which may precipitate multiorgan failure and death. ALF is often associated with impaired β-oxidation and increased oxidative stress (OS), characterized by elevated levels of hepatic reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Peroxisome proliferator-activated receptor (PPAR)α has been shown to confer hepatoprotection in acute and chronic liver injury, at least in part, related to its ability to control peroxisomal and mitochondrial β-oxidation.

The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice.

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms.

Giardia muris infection in mice is associated with a protective interleukin 17A response and induction of peroxisome proliferator-activated receptor alpha.

The protozoan parasite Giardia duodenalis (Giardia lamblia) is one of the most commonly found intestinal pathogens in mammals, including humans. In the current study, a Giardia muris-mouse model was used to analyze cytokine transcription patterns and histological changes in intestinal tissue at different time points during infection in C57BL/6 mice. Since earlier work revealed the upregulation of peroxisome proliferator-activated receptors (PPARs) in Giardia-infected calves, a second aim was to investigate the potential activation of PPARs in the intestines of infected mice.

PPARalpha regulates the production of serum Vanin-1 by liver.

The membrane-bound Vanin-1 pantetheinase regulates tissue adaptation to stress. We investigated Vnn1 expression and its regulation in liver. Vnn1 is expressed by centrolobular hepatocytes.

Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

Objective: Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed.

LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice.

Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions.

Atheroprotective effect of human apolipoprotein A5 in a mouse model of mixed dyslipidemia.

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)ApoA5 on atherogenesis. The influence of hApoA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia.

Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha.

Background & Aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erbalpha is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogenesis. Here, we investigate a potential role for Rev-erbalpha in the control of bile acid metabolism via the regulation of the neutral bile acid synthesis pathway.

Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.

The acute-phase response is characterized by the modulation of liver expression of many proteins involved in a diversity of biological functions. Among them, some are associated with the pathology of atherosclerosis. We previously found that peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists attenuate the IL-6 induction of acute-phase response gene expression in vitro and in vivo.

Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice.

Objective: In this article, we studied the effect of acetyl-11-keto-beta-boswellic acid (AKbetaBA), a natural inhibitor of the proinflammatory transcription factor NF-kappaB on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/-) mice.

Methods And Results: Atherosclerotic lesions were induced by weekly LPS injection in apoE-/- mice. LPS alone increased atherosclerotic lesion size by approximately 100%, and treatment with AKbetaBA significantly reduced it by approximately 50%.

Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.

Overexpression of human APOA5 in mice results in dramatically decreased plasma triglyceride levels. In this study we explored the mechanism underlying this hypotriglyceridemic effect. Initially we found that triglyceride turnover was faster in hAPOA5 transgenic mice compared to controls, and this strongly correlated with increased LPL activity in postheparin plasma.

Analysis of apolipoprotein A5, c3, and plasma triglyceride concentrations in genetically engineered mice.

Objective: Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations.

Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels.