The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans (pdf)

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The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans

Adv Ther (2016) 33:291–319 DOI 10.1007/s12325-016-0306-9 REVIEW The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans Stefano Ballestri . Fabio Nascimbeni . Dante Romagnoli . Enrica Baldelli . Amedeo Lonardo To view enhanced content go to www.advancesintherapy.com Received: December 2, 2015 / Published online: February 26, 2016 Ó Springer Healthcare 2016 ABSTRACT Nonalcoholic describes (NRs) are transcriptional factors which, activated by ligands, are master regulators of fatty liver steatosis, disease (NAFLD) nonalcoholic metabolism and also have intricate connections with circadian control accounting for cyclical steatohepatitis with or without fibrosis, and patterns in the metabolic fate of nutrients. hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though Several transcription factors, peroxisome proliferator-activated observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate disease. NAFLD, which is a major public health energetic issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors Dysregulation of such pathways is heavily implicated in those metabolic derangements S. Ballestri and F. Nascimbeni contributed equally to this work. fluxes and metabolic such as receptors, pathways. characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0306-9) contains supplementary material, which is available to authorized users. NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history S. Ballestri Pavullo Hospital, Azienda USL Modena, Modena, Italy of drug agonists or antagonists of the NRs F. Nascimbeni D. Romagnoli A. Lonardo (&) NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy e-mail: ; F. Nascimbeni E. Baldelli University of Modena and Reggio Emilia, Modena, Italy of human NAFLD. Next, we discuss the results observed in humans following administration pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined. Keywords: Cirrhosis; Farnesoid X receptor; Fibrosis; Hepatocellular carcinoma; Liver X Adv Ther (2016) 33:291–319 292 receptor; Natural history; Nonalcoholic linked to IR/T2D and atherogenic dyslipidemia steatohepatitis; Pathogenesis; Peroxisome proliferator-activated receptor; Steatosis [13, 15]. INTRODUCTION regulators of metabolism and also have intricate connections with circadian control accounting Nonalcoholic fatty liver disease (NAFLD) designates a heterogenous set of diseases for cyclical patterns in the metabolic fate of Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master histologically mimicking alcoholic liver disease nutrients [16]. Several transcription factors, such as peroxisome proliferator-activated though observed in insulin-resistant nonalcoholic individuals, in the absence of receptors (PPARs), liver X receptors (LXRs), and farnesoid X receptors (FXRs), finely competing etiologies of liver disease [1, 2]. The NAFLD spectrum and its natural history span regulate energetic fluxes and metabolic nonalcoholic pathways via the molecular cascades they trigger [17]. Dysregulation of such pathways is steatohepatitis (NASH), fibrosis-cirrhosis, and, in a subset of cases, hepatocellular carcinoma heavily implicated in those metabolic derangements typically belonging to the (HCC), with or without cirrhosis [3, 4]. On the basis of the epidemic prevalence of disease and domain of IR and MetS and in the histogenesis simple steatosis through its inherent hepatic, metabolic, oncologic, and of progressive NAFLD forms and their clinical complications in both adults and children [3, cardiovascular disease burden, NAFLD is a major public health issue posing heavy costs on health 16, 18, 19]. On these systems [1, 5–7]. From a pathophysiological point of view, pharmacological manipulation of NRs has become a major aim in the research intrahepatic storage of triglycerides (TGs) is an example of an adaptive process becoming concerning NAFLD treatment. The present grounds, dietary and maladaptive, given that ectopic fat gives rise article critically reviews the role of NRs in the pathogenesis of NAFLD and explores how this to lipotoxicity [8, 9]. Fatty changes will primarily result from excess de novo information may potentially be exploited in the drug treatment of this condition. All of these intrahepatic lipogenesis associated with the liver being overwhelmed by an excess of pieces of information may be put into steatogenic substrates in the setting of insulin perspective on the basis of the analysis of the natural history of NAFLD (Fig. 1). resistance (IR), impaired glucose disposal/type 2 diabetes (T2D), hyperlipidemia, visceral obesity, This article is based on previously conducted studies and does not involve any new studies of and other features of the metabolic syndrome (MetS) [10]. Steatosis will also derive from the human or animal subjects performed by any of the authors. failure of the liver to oxidize and export excess lipids [3, 11–13]. Therefore, NAFLD can best be conceptualized as an abnormal storage of TGs PATHOPHYSIOLOGY OF PPARs resulting from an imbalance between intrahepatic synthesis and catabolism/disposal The PPARs are members of the NR superfamily of fatty substrates [14], which is inextricably including PPAR-a, PPAR-b/d, and PPAR-c, which play a key role in regulating cellular growth and Adv Ther (2016) 33:291–319 293 PATHOPHYSIOLOGY NATURAL COURSE Steatosis Glycolisis FA ß-oxidaon PPAR-α/δ: Elaﬁbranor FA ß-oxidaon Steatosis LXR PPAR-α: Fibrates, PUFA PPAR-γ: Thiazolidinediones PPARs TG storage Adiponecn DRUG TREATMENT Inﬂammaon Fibrosis SR9238? cholesterol FA Fibrosis FXR Obecholic Acid Bile Acids Fig. 1 Overview of the role of nuclear receptors in the pathophysiology, natural course, and treatment of NAFLD based on data discussed in the present review article. This cartoon aims to summarize the speciﬁc roles played by PPARs, FXR, and LXR in the development and progression of NAFLD. Pathophysiology PPAR-a promotes b-oxidation of FA in the hepatocytes and exerts lipid-lowering activity; PPAR-c, abundantly expressed in the adipose tissue, promotes adipocyte differentiation and storage of triglycerides and has an insulin-sensitizing activity by protecting non-adipose tissues against excessive fat deposition and by increasing adiponectin secretion; PPAR-b/ d stimulates glycolysis and inhibits gluconeogenes (...truncated)