Insights into the role of hepatocyte PPARα activity in response to fasting

Régnier, Marion; Polizzi, Arnaud; Lippi, Yannick; Fouché, Edwin; Michel, G.; Lukowicz, Céline; Smati, Sarra; Marrot, Alain; Lasserre, Frédèric; Naylies, Claire; Batut, Aurélie; Viars, Fanny; Bertrand‐Michel, Justine; Postic, Catherine; Loiseau, Nicolas; Wahli, Walter; Guillou, Hervé; Montagner, Alexandra

doi:10.1016/j.mce.2017.07.035

Cited by 47 publications

(58 citation statements)

References 68 publications

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“…PPARA plays a major role in regulating global lipid homeostasis. Other studies have assessed the role of PPARA during the fasting response with particular focus on the liver (17,18). Interestingly, these studies are influenced by several factors, including fasting regimen, animal age, and diet, leading to inconsistencies in reproducibility between laboratories.…”

Section: Discussionmentioning

confidence: 99%

Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

Brocker

Patel

Velenosi

et al. 2018

Journal of Lipid Research

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PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT ( ), total body-null ( ), and hepatocyte-specific-null ( ) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in versus mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in mice. In mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

Brocker

Patel

Velenosi

et al. 2018

Journal of Lipid Research

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“…PPARα is the most abundant PPAR isotype in the healthy liver 17 and in hepatocytes, PPARα regulates the expression of thousands of genes and contributes to the remarkable metabolic flexibility of the liver [18][19][20][21] . PPARα is particularly active during suckling [22][23][24] and fasting 19,20,[25][26][27][28] , two conditions in which fatty acids are a preferred source of energy for the organism. PPARα is also expressed in many other tissues, including skeletal muscle 29 , adipose tissues [30][31][32][33] , intestine 34 , heart 35 , and kidney 36 .…”

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confidence: 99%

Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity

Régnier

Polizzi

Smati

et al. 2020

Sci Rep

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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 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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“…PPAR, and other PPAR isotypes represent targets currently being tested in clinical trials [9,51,52]. PPAR is a ligandactivated nuclear receptor that plays a key role in the regulation of metabolic homeostasis by modulating the expression of rate-limiting enzymes involved in fatty acid degradation [17][18][19].…”

Section: Discussionmentioning

confidence: 99%

“…PPAR is the most abundant PPAR isotype in the healthy liver [16] and in hepatocytes, PPAR regulates the expression of thousands of genes and contributes to the remarkable metabolic flexibility of the liver [17][18][19][20]. PPAR is particularly active during suckling [21][22][23] and fasting [18,19,[24][25][26][27], two conditions in which fatty acids are a preferred source of energy for the organism. PPAR is also expressed in many other tissues, including skeletal muscle [28], adipose tissues [29][30][31][32], intestine [33], heart [34], and kidney [35].…”

Section: Introductionmentioning

confidence: 99%

“…Germline deletion of Ppar renders mice susceptible for many metabolic defects including obesity [36], steatosis [36,37], and NASH [38,39], but not diabetes [40,41]. We have showed recently that a hepatocyte-specific deletion of Ppar induces spontaneous steatosis in aging mice and blunts fasting-induced ketogenesis [18,19]. Moreover PPAR is required for the expression of fibroblast growth factor 21 (FGF21) [42,43], a liver-derived hormone with many endocrine [44] and hepatoprotective effects [45,46].…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

Régnier

Polizzi

Smati

et al. 2018

Preprint

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Objectives: Peroxisome proliferator activated receptor  (PPAR) 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 Ppar in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it 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. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPAR in a preclinical model of steatosis. Methods/Results: We have investigated the role of hepatocyte PPAR in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Ppar -/-) mice and in mice lacking Ppar in hepatocyte (Ppar hep-/-). We provide evidence that Ppar deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR activity predominantly contributes to the metabolic response to HFD. Conclusion: Taken together, our data support hepatocyte PPAR as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPAR activity contributes to whole-body lipid homeostasis. Highlights  Ppar deletion in hepatocytes promotes steatosis and inflammation in HFDinduced obesity  Hepatocyte-specific deletion of Ppar dissociates NAFLD from glucose intolerance in HFD-induced obesity  Extrahepatic PPAR activity contributes to the metabolic response to HFDinduced obesity WT, Ppar -/-and Ppar hep-/mice were fed a standard diet (Safe 04 U8220G10R) until 8 weeks old, when the mice were fed a high fat diet (D12492, Research Diet) containing 60% calories from fat (lard), 20% calories from carbohydrates (7% sucrose) and 20% calories from proteins; or a chow diet (D12450J, Research Diet) containing 10% calories from fat, 70% Dietcalories from carbohydrates (7% sucrose) and 20% calories from protein during 12 weeks (until 20 weeks old). Experimental groups were designed as follows: WT CTRL, 8 mice; WT HFD, 8 mice; Ppar hep-/-CTRL, 10 mice; Ppar hep-/-HFD, 9 mice; Ppar -/-CTRL, 10 mice; Ppar -/-HFD, 10 mice.

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Insights into the role of hepatocyte PPARα activity in response to fasting

Cited by 47 publications

References 68 publications

Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

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