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Section from a non alcoholic steatotic liver in the absence of PPAR. © INRA, Alexandra Montagner

Liver metabolic disease: a key factor identified

Non alcoholic fatty liver disease (NAFLD) represents a major public health issue as it is currently considered that 20% of the population is at risk in industrialized countries. While NAFLD can remain benign, it predisposes people to more severe pathologies such as steatohepatitis and liver cancer. Scientists from INRA (France), in collaboration with Nanyang Technological University’s Lee Kong Chian School of Medicine (LKCMedicine) in Singapore have provided evidence that the suppression of a protein called PPARα in hepatocytes is sufficient to lead to the development of NAFLD. These results are published on February in GUT.

Updated on 09/19/2016
Published on 02/16/2016

Amongst many key functions, the liver plays a critical part in lipid metabolism. Non alcoholic liver disease or fatty liver relates to abnormally elevated lipid storage in this organ, in the absence of excess alcohol intake. This disease has recently become a major public health issue.

PPARs (for “Peroxisome Proliferator-Activated Receptors”) are nuclear receptors expressed in many organs (liver, adipose tissues, kidney, muscles…). Stimulated by binding to lipids (fatty acids and their derivatives), a number of drugs and endocrine disruptors (food contaminants), they regulate the expression of a subset of target genes.

In order to investigate the role of PPARα in liver lipid accumulation, a group of scientists from INRA and LKCMedicine has developed a mouse model lacking the receptor, specifically in the liver.

The lack of PPARα in hepatocytes promotes Non Alcoholic Fatty Liver Disease

This original model allows scientists to determine that the absence of the receptor in hepatocytes disrupt fatty acid breakdown and leads to lipid deposition in the liver in response to fasting or to diets enriched in dietary fat. Moreover, animals lacking the receptor spontaneously developed the disease in aging without being overweight and diabetic. This work reveals that the receptor PPARα controls the specific expression pattern of the hormone FGF21 over the day. FGF21 is known for its impacts on health, including growth, fertility, metabolism, and longevity.

The circadian PPARα activity is sensitive to adipocyte lipolysis and gut microbiota

The results published in Gut further our knowledge about the autonomous activities of the receptor in hepatocytes and provide evidence that PPARα is required for the dialog between the liver and the white adipose tissues. Moreover, another recent publication from the same groups (Scientific reports) establishes that PPARα is sensitive to signals derived from the microbiota, the bacterial community hosted in the gut. More broadly, the gut microbiota regulates circadian liver activities such as the production of metabolites and hormones, including FGF21.

Altogether, these works further define the role of PPARα in hepatocytes as an integrator of multiple signals required for normal liver function. They open new perspectives of our understanding of the receptor, its influence during the perinatal period, its role in Type 2 diabetes, its tissue-specific activities and its interaction with other members of the PPAR family.

For INRA, this is very important since PPARs are critical nutritional (dietary lipids) and xenobiotic (food contaminants) sensors. The use of PPAR ligands as drugs for metabolic diseases is highly relevant to the current research at LKCMedicine.

Section from a non alcoholic steatotic liver in the absence of PPAR. © INRA, Alexandra Montagner
Section from a non alcoholic steatotic liver in the absence of PPAR © INRA, Alexandra Montagner

Scientific contact(s):

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INRA News Office (33 (0)1 42 75 91 86)
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“Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD”
Alexandra Montagner, Arnaud Polizzi, Edwin Fouche, Simon Ducheix, Yannick Lippi, Frederic Lasserre, Valentin Barquissau, Marion Regnier, Celine Lukowicz, Fadila Benhamed, Alison Iroz, Justine Bertrand-Michel, Talal Al Saati, Patricia Cano, Laila Lakhal, Gilles Mithieux, Fabienne Rajas, Sandrine Lagarrigue, Thierry Pineau, Nicolas Loiseau, Catherine Postic, Dominique
Langin, Walter Wahli, Herve Guillou
Gut | 2016 Feb 1 | doi: 10.1136/gutjnl-2015-310798

“Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals”
Alexandra Montagner, Agata Korecka, Arnaud Polizzi, Yannick Lippi, Yuna Blum, Cécile Canlet, Tremblay-Franco Marie, Gautier-Stein Amandine, Rémy Burcelin, Yi-Chun Yen, Hyunsoo Shawn Je, Al-Asmakh Maha, Gilles Mithieux, Velmurugesan Arulampalam, Sandrine Lagarrigue, Hervé Guillou, Sven Pettersson & Walter Wahli
Scientific Reports | 6:20127 | DOI: 10.1038/srep20127