The transcription factor HNF-4α: a key factor of the intestinal uptake of fatty acids in mouse

Frochot, Vincent; Alqub, Malik; Cattin, Anne-Laure; Carrière, Véronique; Houllier, Anne; Baraille, Floriane; Barbot, L.; Saint-Just, Susan; Ribeiro, Agnès; Lacasa, Michel; Cardot, Philippe; Chambaz, Jean; Rousset, Monique; Lacorte, Jean‐Marc

doi:10.1152/ajpgi.00329.2011

Cited by 27 publications

(19 citation statements)

References 50 publications

(36 reference statements)

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“…HNF4A has been characterized as a master metabolic regulator for its conserved roles in gluconeogenesis, glucose homeostasis, and fatty acid metabolism (Palanker et al 2009;Frochot et al 2012;Barry and Thummel 2016). Despite its clear importance in metabolic health, relatively little insight into its regulation in a biological context has been reported.…”

Section: Discussionmentioning

confidence: 99%

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

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Section: Discussionmentioning

confidence: 99%

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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“…Following centrifugation of blood samples, plasma was used for triglyceride measurements using a kit from DiaSys (DiaSys, Condom, France) according to the manufacturer's instructions. Intestinal epithelial cells were prepared as described previously (24). Briefly, the jejunum was cut into small pieces and incubated at 4°C for 2 h in 3 ml of cell recovery solution (BD Biosciences, Le Pont de Claix, France) containing protease and phosphatase inhibitor mixtures (Roche Diagnostics, Meylan, France).…”

Section: Methodsmentioning

confidence: 99%

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Tran¹,

Postal²,

Demignot³

et al. 2016

Journal of Biological Chemistry

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The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulinsignaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance. As compared with the liver, pancreas, muscle, or adipose tissues, the intestine has received little attention with regard to its potential role in the onset of metabolic disorders. Nevertheless, the intestine could also contribute to the development of metabolic disease, especially through its role in postprandial lipemia.The increased amplitude and duration of the postprandial peak of circulating triglyceride-rich lipoproteins (TRL) 5 are known risk factors for atherosclerosis and cardiovascular diseases (1, 2). Postprandial hypertriglyceridemia can be due to impaired TRL catabolism, and/or lipoprotein remnant uptake, and may also result from intestinal TRL overproduction (3). Thus, investigating intestinal lipoprotein secretion might help to understand aberrant postprandial lipemia (4).The intestine ensures the transport of alimentary fat, which is the most calorie-dense nutrient. Enterocytes produce intestinal TRLs (chylomicrons) along a multistep pathway, which includes long chain fatty acid uptake, triglyceride synthesis in the endoplasmic reticulum, and assembly with apolipoproteins (apo) such as apoB48. Chylomicrons are then secreted into the lymph and ultimately into the blood. Overproduction of intestinal TRL may be an important contributor of both fasting and postprandial dyslipidemia (3, 5). Microsomal triglyceride transfer protein (MTP) transports neutral lipids (6) and plays a cen...

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“…Specific intestinal Hnf4a gene invalidation in adult mice (Hnf4a Dint ) was described previously (22,23,26). For experiments, 6-month-old male control Hnf4a loxP/loxP and Hnf4a loxP/loxP /villin-CreERT2 mice received tamoxifen treatment (23), and analyses were performed 10 days later.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…For experiments, 6-month-old male control Hnf4a loxP/loxP and Hnf4a loxP/loxP /villin-CreERT2 mice received tamoxifen treatment (23), and analyses were performed 10 days later.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…We reported previously that HNF-4a is expressed in intestinal crypts and villi, whereas the g form is restricted to villi (21). These different distributions combined with the absence of compensation by HNF-4g for some phenotypic traits of intestinal Hnf4a knockout mice, namely impairment of intestinal epithelium homeostasis, cell architecture, and fatty acid uptake (22)(23)(24), suggest that the a and g forms play specific and different roles in intestine.…”

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confidence: 96%

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Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF-4γ: A Critical Role for Enteroendocrine Cell Lineage

et al. 2015

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Intestine contributes to energy homeostasis through the absorption, metabolism, and transfer of nutrients to the organism. We demonstrated previously that hepatocyte nuclear receptor-4a (HNF-4a) controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4g, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4g knockout mice, we detect an exaggerated insulin peak and improvement in glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2, and Hnf4a, leading to an increase of both GLP-1-positive cell number and basal and stimulated GLP-1 plasma levels potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin (9-39), we demonstrate a direct effect of GLP-1 on improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic b-cells, and we report an increase of the b-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4g improves glucose homeostasis through a modulation of the enteroendocrine cell lineage.During past decades, changes in dietary habits, including increments in calorie and saturated fatty acid intake, have occurred concomitantly with a rise of metabolic diseases, such as diabetes, obesity, and the metabolic syndrome (1). These metabolic disorders, which are known risk factors for cardiovascular diseases, represent emerging medical and public health concerns. Intestine, which is the first organ facing digestion products and which contributes to energy homeostasis through the transfer of nutrients to the organism, receives little attention about its potential role in the onset of metabolic disorders compared with liver, pancreas, muscle, and adipose tissue.

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The transcription factor HNF-4α: a key factor of the intestinal uptake of fatty acids in mouse

Cited by 27 publications

References 50 publications

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF-4γ: A Critical Role for Enteroendocrine Cell Lineage

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