Abstract
A long neglected hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) arise as serious health burden with alarming global prevalence. The disease complex is currently attracting considerable interest of drug discovery and many experimental approaches are studied in all stages of clinical development. Peroxisome proliferator-activated receptors (PPARs) have a successful history as pharmaceutical targets in the treatment of several aspects of the metabolic syndrome and, therefore, a putative therapeutic value of PPAR modulators in NAFLD/NASH is obvious. However, so far only the PPARα/δ agonist elafibranor has revealed clear efficacy and reached an advanced stage of development while the far more established PPAR subtypes PPARα and PPARγ have disappointed. Still, clinical trial design and population might have obscured beneficial activities and, in addition, synergistic multi-target approaches as well as selective PPAR modulators could generate safer approaches with higher therapeutic efficacy.
Highlights
Non-alcoholic steatohepatitis (NASH) is the long-term consequence of non-alcoholic fatty liver disease (NAFLD)
PPARγ agonistic thiazolidinediones markedly improved the therapy of type 2 diabetes mellitus as insulin sensitizers but few years ago their therapeutic significance ended with market withdrawals and warnings due to severe side effects
PPARδ was considered as very promising target to treat metabolic disorders until the first selective PPARδ agonist GW501516 failed in clinical trials due to unresolved safety concerns
Summary
Non-alcoholic steatohepatitis (NASH) is the long-term consequence of non-alcoholic fatty liver disease (NAFLD). Hepatocellular injury [4] and hepatocyte ballooning occur the disease progresses to NASH that may lead to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) [5, 6]. Nuclear receptors have high significance amongst the experimental targets studied for NASH and as well-established targets in the treatment of metabolic diseases. PPARs have been evaluated for the therapeutic potential as well. The available data of PPAR modulation in the disease complex NAFLD and NASH will be focus of this review. How to cite this article: Leonie Gellrich and Daniel Merk, “Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis,” Nuclear Receptor Research, vol 4, Article ID 101310, 52 pages, 2017. How to cite this article: Leonie Gellrich and Daniel Merk, “Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis,” Nuclear Receptor Research, vol 4, Article ID 101310, 52 pages, 2017. doi:10.11131/2017/101310
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