ObjectivePeroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).DesignWe constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.ResultsHepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing.ConclusionsAltogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.

SummaryWhile the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.

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 Pparαdeficient 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. Non alcoholic fatty liver disease (NAFLD) has become a major public health concern worldwide 1. NAFLD ranges from benign steatosis to non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis or hepatocarcinoma. The hallmark of NAFLD is an elevated level of neutral lipids, which accumulate as lipid droplets in hepatocytes 2. Although the aetiology of the disease is not fully understood, it is strongly associated with obesity and type 2 diabetes (T2D). In human NAFLD, the fatty acids that accumulate in hepatocytes originate from dietary fat 3,4 , adipose tissue lipolysis and hepatic de novo lipogenesis 3. In T2D, adipose tissue insulin resistance promotes lipolysis, whereas hyperglycaemia combined with hyperinsulinemia sustains hepatic de novo lipogenesis 5. Given the burden of the NAFLD epidemic, identifying molecular players that can be targeted is a rather important issue 6,7. Moreover, finding drugs that may be used to treat NASH and its progression to irreversible liver disease is a so far unmet medical need to be solved 8,9. Among drugs currently being tested in clinical trials

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The incidence of inflammatory bowel diseases (IBD) is increasing inboth Western and developing countries. IBD are multifactorial disorders involving complex interactions between genetic, immune, and environmental factors such as exposure to food contaminants. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food and induces intestinal breakdown and inflammatory response. To delineate the role of DON oral exposure in IBD, we used a Dextran sulfate sodium (DSS) colitis model in rats fed with a DONcontaminated diet or a control diet for four weeks. Colitis was induced in the third week by increasing concentrations of DSS in the drinking water (0, 2, 3 or 5%). DON exacerbated body weight loss and accelerated the appearance of symptoms in animals treated with DSS. DON increased morphological damage, pro-inflammatory markers (myeloperoxidase, CXCL1 and IL1β) and immune cell responses. In lamina propria of rat with colitis, DON increased adaptive and innate immune responses after anti-CD3/28 or LPS stimulation, respectively. In spleen, DON increased IFNγ secretion and reduced Treg populations. Interestingly, De-epoxy-DON (DOM-1) a detoxified form of DON did not have any consequences on colitis. These results suggest that DON is a risk factor in the onset of IBD.

In Burkina Faso, as in most Sahelian countries, the failure to follow good agricultural practices coupled with poor soil and climate conditions in the locust control context lead to high environmental contaminations with pesticide residues. Thus, consumers being orally exposed to a combination of multiple pesticide residues through food and water intake, the digestive tract is a tissue susceptible to be directly exposed to these food contaminants. The aim of our work was to compare in vitro the impact of five desert locust control pesticides (Deltamethrin DTM, Fenitrothion FNT, Fipronil FPN, Lambda-cyalothrine LCT, and Teflubenzuron TBZ) alone and in combination on the human intestinal Caco-2 cells viability and function. Cells were exposed to 0.1–100 μM pesticides for 10 days alone or in mixture (MIX). Our results showed a cytotoxic effect of DTM, FNT, FPN, LCT, and TBZ alone or in combination in human intestinal Caco-2 cells. The most efficient were shown to be FPN and FNT impacting the cell layer integrity and/or barrier function, ALP activity, antioxidant enzyme activity, lipid peroxidation, Akt activation, and apoptosis. The presence of antioxidant reduced lipid peroxidation level and attenuated the pesticides-induced cell toxicity, suggesting that key mechanism of pesticides cytotoxicity may be linked to their pro-oxidative potential. A comparative analysis with the predicted cytotoxic effect of pesticides mixture using mathematical modeling shown that the combination of these pesticides led to synergistic effects rather than to a simple independent or dose addition effect.

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