Role for PPARγ in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts

Abstract

Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear receptor central to glucose and lipid homeostasis. PPARγ role in nonalcoholic fatty liver disease is controversial because PPARγ overexpression is a general property of steatotic livers, but its activation by thiazolidinediones reduces hepatic steatosis. Here, we investigated hepatic PPARγ function by using Cre-loxP technology to generate hepatocyte (PPARγ(Δhep))- and macrophage (PPARγ(Δmac))-specific PPARγ-knockout mice. Targeted deletion of PPARγ in hepatocytes, and to a lesser extent in macrophages, protected mice against high-fat diet-induced hepatic steatosis. Down-regulated expression of genes involved in lipogenesis (SCD1, SREBP-1c, and ACC), lipid transport (CD36/FAT, L-FABP, and MTP), and β-oxidation (PPARα and ACO) was observed in PPARγ(Δhep) mice. Moreover, PPARγ(Δhep) mice showed improved glucose tolerance and reduced PEPCK expression without changes in Pcx, Fbp1, and G6Pc expression and CREB and JNK phosphorylation. In precision-cut liver slices (PCLSs) and hepatocytes, rosiglitazone either alone or in combination with oleic acid increased triglyceride accumulation, an effect that was blocked by the PPARγ antagonist biphenol A diglycidyl ether (BADGE). PCLSs and hepatocytes from PPARγ(Δhep) mice showed blunted responses to rosiglitazone and oleic acid, whereas the response to these compounds remained intact in PCLSs from PPARγ(Δmac) mice. Collectively, these findings establish PPARγ expression in hepatocytes as a prosteatotic factor in fatty liver disease.

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

“…This observation is recapitulated in humans, as obese patients with hepatosteatosis exhibited markedly increased PPAR-␥ activity in the liver (53,54). Conversely, mice with liver-specific Ppar-␥ deletion are refractory to fat-induced steatosis, due to the reduction of lipogenesis in the liver (42,47). Thus, ATF4 may act through PPAR-␥ to modulate hepatic lipid metabolism in ATF4-deficient mice.…”

“…3I). Furthermore, we quantified hepatic expression levels of Ppar-␥, a nuclear receptor whose activation is linked to enhanced lipid synthesis and increased fat storage in the liver (42)(43)(44). We detected a significant reduction in hepatic Ppar-␥ expression (Fig.…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…PPARa is integral to limiting hepatic lipid accumulation by upregulating pathways that allow for fatty acid oxidation, ketogenesis and fatty acid export (Rakhshandehroo et al 2007), while PPARg encourages fatty acid storage by upregulating lipogenic genes including fatty acid transporters and enzymes in fatty 234:1 acid and triglyceride synthesis (Schadinger et al 2005). However, in fatty liver disease, PPARg can also upregulate traditionally PPARa target genes (Patsouris et al 2006, Moran-Salvador et al 2011. Hepatic-specific PPARg knockout protects high-fat diet-fed mice from hepatic lipid accumulation, improves glucose tolerance and prevents upregulation of lipogenic, beta-oxidative and gluconeogenic genes (Moran-Salvador et al 2011).…”

“…However, in fatty liver disease, PPARg can also upregulate traditionally PPARa target genes (Patsouris et al 2006, Moran-Salvador et al 2011. Hepatic-specific PPARg knockout protects high-fat diet-fed mice from hepatic lipid accumulation, improves glucose tolerance and prevents upregulation of lipogenic, beta-oxidative and gluconeogenic genes (Moran-Salvador et al 2011). Thus, induction of both PPARg and PPARa by hepatic lipid accumulation directs hepatic metabolic flux toward hepatic glucose and ketone production.…”

La sphingosine kinase 1 : rôle dans la stéatose hépatique

“…‡ Sphingosine kinase-1: role in non alcoholic fatty liver disease Conclusions et perspectives L'ensemble de ces résultats suggèrent un rôle de la SphK1 dans la stéatose hépatique via un mécanisme dépen-dant des récepteurs S1P 2 et S1P 3 et de l'activation de PPAR (Figure 1). Dans le foie, PPAR est exprimé dans les cellules de Kupffer (macrophages spécialisés) et les hépatocytes, mais l'activation de PPAR dans les cellules de Kupffer n'est pas essentielle au développement initial de la stéatose hépatique [12], suggérant que la régu-lation de PPAR par la SphK1 se fait au niveau des hépatocytes. Néanmoins, le rôle de la SphK1 dans les cellules de Kupffer, elles-mêmes impliquées dans la stéatose hépatique, reste encore à déterminer, et en particulier son rôle pro-inflammatoire [13].…”