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

Abstract

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.

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD)

“…Remarkably, diet and genetic PPARα knockout mice elicit similar transcriptional activation of multiple transcription factors, steroid hormone receptors and epigenetic factors involved in metabolic stress responses in the liver (Figures 3A, B). This is not completely unexpected, since loss of hepatocyte PPARα function results in loss of lipid metabolism homeostasis due to impaired fatty acid, bile acid and amino acid catabolic processes (Figure 1D) which results in major changes in the lipidome composition (Régnier et al, 2020). Accordingly, multiple compensation mechanisms of lipid sensing transcription factors and nuclear hormone receptors (Myc, NR4A1, NR4A3, PPARδ/γ, E2F1, PPARGC1B, Nrf2/NFE2L2, TCF21) are activated to mitigate lipidomic stress and to alleviate mitochondrial metabolic stress (Walczak and Tontonoz, 2002;Zirath et al, 2013;Denechaud et al, 2015;Sharma et al, 2018;Yan et al, 2018;Li et al, 2020;Cariello et al, 2021;Mohs et al, 2021;Ni et al, 2023).…”

A Newly Synbiotic Combination Alleviates Obesity by Modulating the Gut Microbiota–Fat Axis and Inhibiting the Hepatic TLR4/NF‐κB Signaling Pathway

“…[69,70] These findings may be subject to hepatic homeostasis of fatty acid catabolism. [71] In fact, liver PPAR-𝛼 is essential for overall fatty acid homeostasis. [72] A high-fat diet induces hepatic PPAR-𝛼 activation, which accelerates fatty acid oxidation, helping to restore energy homeostasis and supplying other tissues with energy.…”

Insights in Atherosclerosis and Vascular Medicine: 2022

“…Among the three PPAR isotypes (PPARα, PPARβ/δ and PPARγ), PPARα is the most abundant in hepatocytes where it acts as a master regulator of mitochondrial/ peroxisomal FAO (356). In mice, hepatocyte-specific loss of PPARα enhances steatohepatitis, which is aggravated in wholebody Ppara −/− mice, indicating a protective role for both hepatic and extrahepatic PPARα in NASH (357)(358)(359). Accordingly, the PPARα agonist, Wy-14,643, lowers MCD diet-induced NASH and fibrosis in mice (360).…”