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Fatty Liver Disease (Nafld/Nash) CAYMANCURRENTS ISSUE 31 | WINTER 2019 FATTY LIVER DISEASE (NAFLD/NASH) Targeting Insulin Resistance for the Metabolic Homeostasis Targets Treatment of NASH Page 6 Page 1 Special Feature Inside: Tools to Study NAFLD/NASH A guide to PPAR function and structure Page 3 Pathophysiology of NAFLD Infographic Oxidative Stress, Inflammation, and Apoptosis Targets Page 5 Page 11 1180 EAST ELLSWORTH ROAD · ANN ARBOR, MI 48108 · (800) 364-9897 · WWW.CAYMANCHEM.COM Targeting Insulin Resistance for the Treatment of NASH Kyle S. McCommis, Ph.D. Washington University School of Medicine, St. Louis, MO The obesity epidemic has resulted in a dramatic escalation Defects in fat secretion do not appear to be a driver of in the number of individuals with hepatic fat accumulation hepatic steatosis, as NAFLD subjects display greater VLDL or steatosis. When not combined with excessive alcohol secretion both basally and after “suppression” by insulin.5 consumption, the broad term for this spectrum of disease Fatty acid β-oxidation is decreased in animal models and is referred to as non-alcoholic fatty liver disease (NAFLD). humans with NAFLD/NASH.6-8 A significant proportion of individuals with simple steatosis will progress to the severe form of the disease known as ↑ Hyperinsulinemia Insulin resistance non-alcoholic steatohepatitis (NASH), involving hepatocyte Hyperglycemia damage, inflammation, and fibrosis. If left untreated, Adipose lipolysis NASH can lead to more severe forms of liver disease such Steatosis as cirrhosis, hepatocellular carcinoma, liver failure, and De novo O ↑ lipogenesis HO eventually necessitate liver transplantation. Due to this large clinical burden, research efforts have greatly expanded Fatty acids to better understand NAFLD pathogenesis and the mechanisms underlying the transition to NASH. Likewise, there are currently no approved agents for treating NAFLD/ NASH, thus efforts to identify therapeutic targets and progress drug development have intensified in recent years. Figure 1. Insulin resistance drives hepatic steatosis. Metabolic syndrome and insulin resistance are the most significant risk factors for the development of NAFLD and PPARs as Drug Targets NASH. Indeed, 60-75% of type 2 diabetic subjects have Because insulin resistance is a direct driver of hepatic lipid NAFLD.1,2 Many aspects of the pathophysiology of insulin accumulation and NASH pathology, the insulin sensitizing resistance are directly causal to NAFLD development thiazolidinedione compounds (TZDs) were one of the (Figure 1). Insulin-resistant adipose tissue is unable to earliest classes of drugs to be tested in NASH. Rosiglitazone appropriately inhibit lipolysis, and therefore, plasma free and pioglitazone have both been used in animal models fatty acid delivery to the liver is increased. In exquisite and human trials of NASH and improve almost all aspects labeling experiments, plasma free fatty acids were shown to of NASH pathology.9-15 These TZD compounds are comprise the source of ~60% of liver triglyceride (TAG) in agonists of the nuclear transcription factor peroxisome NAFLD subjects.3 Inadequate insulin signaling also results proliferator-activated receptor γ (PPARγ).16 PPARγ regulates in increased insulin secretion from pancreatic β-cells and a gene expression program for adipocyte differentiation hyperinsulinemia, which can stimulate hepatic de novo and fatty acid storage. While lipid “sequestration” into lipogenesis.4 Whether derived from free fatty acids or adipose tissue could be protective against hyperlipidemia, de novo lipogenesis, these lipids are largely converted to this PPARγ activation with TZDs is associated with a acyl-CoAs by acyl-CoA synthetases, complexed to glycerol- number of side effects such as weight gain, edema, and 3-phosphate to create diacylglyceride, and lastly, a third bone mineral density loss and fracture risk,17 which have acyl-CoA is added by diacylglycerol acyltransferase (DGAT) greatly diminished the clinical use of TZDs. Interestingly, to form TAG. This TAG, as well as other lipids and sterols, pioglitazone is a much weaker agonist of PPARγ compared are then stored inside lipid droplets. These lipid-bound to rosiglitazone,16 but provides superior improvements organelles are thought to safely store and control the in NASH histology, particularly with regards to fibrosis hydrolysis of these lipids. While somewhat controversial, improvement.18 These results have opened the door to accumulation of other lipid intermediate species such as the possibility that TZDs could have additional target(s) diacylglycerols, ceramides, and acyl-CoAs in the liver has responsible for their pharmacology. Indeed, it was recently been linked to worsening insulin resistance. Other potential observed that TZDs can bind and inhibit the mitochondrial mechanisms for fat accumulation in hepatocytes include pyruvate carrier (MPC), which regulates pyruvate transport decreased fat oxidation and decreased fat secretion in across the inner mitochondrial membrane into the the form of very low-density lipoprotein (VLDL) particles. mitochondrial matrix.19-21 PPARγ-sparing TZD compounds Cayman Currents 1 Issue 31, Winter 2019 that retain full ability to bind the MPC (MSDC-0602K and inhibition of DGAT-1 or -2 in animal models has been shown MSDC-0160) have been developed.19,22 MSDC-0602K was to improve hepatic steatosis and fibrosis, as well as hepatic recently shown to improve NASH pathology in a mouse and global insulin sensitivity.31-35 Intriguingly, DGAT-2 model23 and is currently in a Phase 2B clinical trial for inhibition was reported to improve steatosis but exacerbate NASH. Inhibiting the MPC may improve NASH pathology hepatic injury in the methionine-choline deficient mouse by improving insulin sensitivity, enhancing fatty acid model of NASH.36 Nevertheless, reducing DGAT expression oxidation, attenuating the upregulated flux of carbon into or activity is still actively being explored to treat NASH, the tricarboxylic acid (TCA) cycle,6,24-26 and reducing hepatic with both small molecule inhibitors and antisense stellate cell activation.23 oligonucleotides in clinical development. Lastly, analogs of Non-TZD compounds have also been developed, which the small secreted peptide encoded in the mitochondrial agonize other PPAR isoforms such as PPARα and PPARδ, genome known as MOTS-c have been developed, which with or without PPARγ activation. In theory, these produce effects similar to insulin action, namely inhibition compounds may combine the insulin-sensitizing effects of of adipose tissue lipolysis. These MOTS-c analogs (CB4209 37 targeting PPARγ with the increased fat oxidation effects of and CB4211) improved NASH histology in a mouse model PPARα and the anti-inflammatory and fatty acid oxidation and will likely progress to clinical trials in the near future. effects of PPARδ. Saroglitazar (PPARα/δ agonist) and IVA337/lanifibranor (pan-PPAR agonist) are currently in Phase 2, while elafibranor (PPARα/δ agonist) is in Phase 3 trials for NASH. Non-PPAR Drug Targets A number of compounds for other targets that improve insulin sensitivity are currently being developed for NASH. Adipose (TAG) Specific Agonists of the farnesoid X receptor (FXR) have been MPC MPC inhibitors Improved insulin Citrate observed to improve insulin sensitivity and provide anti- sensitivity Mitochondria inflammatory and antifibrotic effects in diabetic patients DNL Acyl-CoA Plasma FFA with NASH.27 Obeticholic acid is a synthetic bile acid Thiazolidinediones analog, which is the predominant compound for FXR DAG Multi- or pan- DGAT inhibitor PPARγ DGAT-1/2 agonism. However, a trial for obeticholic acid in NASH was PPAR agonists or antisense oligonucleotide terminated before completion due to low treatment efficacy PPARα PPARδ TAG and side effects such as pruritis and modest LDL cholesterol Bile acids, FXR 28 synthetic FXR agonists, elevations. FXR agonism for NASH will likely depend on and FGFs Nucleus Lipid droplets whether newer synthetic agonists lacking the bile acid structure display benefits without similar side effects. Synthetic derivatives of fibroblast growth factors FGF19 and FGF21 can also regulate hepatic FXR and PPARγ Figure 2. Hepatic targets of insulin sensitizing therapies in development for NASH. coactivator 1 (PGC-1) activity and lead to improved insulin sensitivity and improvements in NAFLD/NASH29 but require Conclusions and Future Outlook larger, longer term trials. These pharmacologic agents that likely have hepatocyte-specific actions in addition to their As insulin resistance and derangements in lipid metabolism overall improved insulin sensitivity are depicted in Figure 2. are so intricately linked to the development of NAFLD, The glucagon-like peptide-1 (GLP-1) receptor agonist it is likely that targeting insulin sensitivity will provide liraglutide predominantly promotes insulin secretion from the broadest spectrum of pharmacology for treating this pancreatic β-cells but can also improve insulin sensitivity.30 disease. While research efforts and compound development GLP-1 receptor agonists provide additional metabolic are active for downstream pathology such as cell stress/ effects, such as weight loss, that could be beneficial in death, inflammation, or antifibrotic compounds, it is NASH. However, these require further clinical testing. hard to envision successful therapeutics that do not also Inhibitors of DGAT-1 or DGAT-2 could potentially improve address the core mechanisms of hepatic lipid accumulation. NASH by preventing TAG formation
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