The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

“…The description of PPARα-target genes shows that this nuclear hormone receptor largely governs those genes involved in hepatic and cardiac muscle transport, oxidation, and the degradation of lipids. Transcriptionally, PPARα activates several genes, including the lipoprotein lipase gene permitting the release of fatty acids from lipoprotein particles [180], genes encoding fatty acid translocase CD36, and fatty acid-binding proteinfacilitating fatty acids capture and transport them through the plasma membrane [8,180]. The acyl-CoA synthetase, activating fatty acids to acyl-CoAs, is another gene-target of PPARα [96,98].…”

“…Thus, in the absence of ACOX1 activity, these dicarboxylic acids are still unmetabolized and act as firm inhibitors of mitochondrial fatty acid β-oxidation [185]. Moreover, the Ppara -/-, Acox1 -/double-knockout mice exhibit a few periportal clusters of steatotic hepatocytes, and (re-)expression of human ACOX1 in mice liver results in a substantial reduction in both PPARα activation and hepatic steatosis [8,180]. Peroxisomal fatty acid β-oxidation is induced by starvation in a PPARα-dependent manner, as validated by its impairment in PPARα null mice [8,180].…”

“…Moreover, the Ppara -/-, Acox1 -/double-knockout mice exhibit a few periportal clusters of steatotic hepatocytes, and (re-)expression of human ACOX1 in mice liver results in a substantial reduction in both PPARα activation and hepatic steatosis [8,180]. Peroxisomal fatty acid β-oxidation is induced by starvation in a PPARα-dependent manner, as validated by its impairment in PPARα null mice [8,180]. Accordingly, the deacetylase sirtuin-1 is dispensable to PPARαinducing peroxisomal fatty acid β-oxidation and needs SIRT1-PPARα interaction, and the deletion of hepatic SIRT1 negatively impacts PPARα signaling [165].…”

Roles of Nuclear Receptors in Vascular Calcification

“…PPARs are lipid-activated NRs regulating lipid and glucose metabolism in metabolic tissues, such as the adipose tissue and the liver [ 106 ]. They are also expressed in cells of the vasculature (endothelial cells, SMC, monocytes/macrophages and lymphocytes), where they mainly control the inflammatory response [ 107 ].…”

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver

“…Their target genes have key roles in both embryonic development and adult homeostasis, and they are collectively implicated in a vast majority, if not all, of the biological processes of the body [ 11 , 17 ]. The hepatic roles of several of these receptors have been reviewed recently and, therefore, will not be discussed herein [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”