Emerging Molecular Targets for the Treatment of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor. 375 A nn u. R ev . M ed . 2 01 0. 61 :3 75 -3 92 . D ow nl oa de d fr om a rj ou rn al s. an nu al re vi ew s. or g by U ni ve rs ita d eg li St ud i D i T or in o D ep ar tm en t o f Pl an t B io lo gy o n 02 /0 9/ 10 . F or p er so na l u se o nl y. AREV402-ME61-25 ARI 6 December 2009 8:29 NAFLD: nonalcoholic fatty liver disease NASH: nonalcoholic steatohepatitis INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease in the world, NAFLD affects 30% of the Western adult population (1) and encompasses a spectrum of histological severity ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter progressing to cirrhosis in 10%–25% of cases over 8–10 years (2). Although its pathogenesis is unclear, NAFLD is tightly associated with overall and central adiposity, insulin resistance, metabolic syndrome, and type 2 diabetes mellitus. MICRORNA BIOGENESIS AND REGULATORY FUNCTION MiRNAs are initially transcribed by RNA polymerase II or III in the nucleus to form large pri-miRNA transcripts, which may be several hundred or thousands of nucleotides long, and are capped (MGpppG) and polyadenylated. The pri-miRNAs are processed in the nucleus by the RNase III enzyme Drosha and by the dsRNA (double-stranded RNA)–binding protein Pasha (also known as DGCR8), into smaller pre-miRNAs, which fold into stem-loop hairpin structures. RanGTP and exportin 5 transport the pre-miRNA into the cytoplasm. Subsequently, another RNase III enzyme, Dicer, processes the pre-miRNA to generate a transient nucleotide duplex. The duplex is loaded into the miRNA-associated miRISC (multiprotein RNA-induced silencing complex), which includes the Argonaute proteins (AGO). One strand of the miRNA is preferentially retained in this complex and becomes the mature miRNA; the opposite strand, known as the passenger strand or miRNA∗, is eliminated from the complex. Some intronic miRNA precursors can bypass Drosha processing to produce miRNAs by Dicer, possibly an alternative pathway for miRNA biogenesis. The mature miRNA binds to complementary sequences in the 30 untranslated regions (30UTRs) of the target mRNAs to regulate gene expression in one of two ways: miRNAs that bind to mRNA targets with imperfect complementarity block target gene expression via translational silencing, whereas miRNAs binding their mRNA targets with perfect complementarity enhance target gene expression. Currently there is no established treatment for NAFLD. Weight loss through lifestyle changes is difficult to achieve and maintain, and thiazolidinediones (a class of insulin sensitizers), a promising drugs for the treatment of NAFLD/NASH, pose weight-gain and longterm safety issues. Therefore, basic research is exploring new molecular mechanisms to target for the treatment of NAFLD and associated disorders.