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

Abstract

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

Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression

“…However, the Insig1 KO livers were protected from ER stress, oxidative damage and inflammation and exhibited reduced fibrogenesis ( Figure 2 I–O). Based on the transcriptional and lipidomic changes that we observed, we speculate that Insig1 KO-mediated “lipo-protection” occurs via optimisation of lipid composition via enhanced production of MUFAs [ 55 , 56 ], other pleiotropic mechanisms that may include improved signalling of PPARs and their co-activator PGC1β [ 39 , 57 ], which were predicted as being upregulated in the Insig1 KO mice ( Figure 2 , Figure 3 , Figure 4 ). In our experimental setting, a significant role seemed to be played by the SREBP1-mediated upregulation of Scd1 and other remodelling enzymes.…”

The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

“…PPARα also attenuates chronic liver inflammation. PPARα deletion in hepatocytes of high-fat fed mice promotes the development of liver inflammation and nonalcoholic fatty liver disease (NAFLD) [112]. Conversely, fenofibrate ameliorated the increased liver inflammatory gene expression and macrophage infiltration in mice with NAFLD [113].…”

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…Liver-specific PPARα-deficiency has revealed the importance of hepatocyte PPARα in protecting the animals from HFD-induced NAFLD, including steatosis and hepatic inflammation [235]. Interestingly, PPARα-null mice and hepatocyte-specific PPARα-deficient mice do not present with increased glucose intolerance when fed a HFD [329]. In addition, hepatocyte-specific deletion of PPARα induces spontaneous steatosis in aging mice and aggravates MCD-induced liver damage [235].…”

“…In humans, liver Gps2 expression positively correlates with NASH and fibrosis [330]. In response to HFD, whole-body and hepatic deficiencies in PPARα differentially alter the lipid profiles, suggesting that extrahepatic PPARα is involved in lipid metabolism and the adaptive response to HFD [329]. PPARα in extrahepatic tissues also contributes to the protection of fasting-induced hepatosteatosis [261].…”