Drug discovery and treatment paradigms in nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western populations, and is closely associated with features of the metabolic syndrome. The burden of disease is set to rise exponentially, and this is further compounded by the lack of good medications. In addition, these patients tend to have multiple comorbidities that may not be adequately managed. In this article, we review the biological basis of potential therapies in nonalcoholic steatohepatitis (NASH), the current drugs being tested in clinical trials, as well some practical considerations in managing patients in the clinic.

Keywords: drug development; drug therapy; nonalcoholic steatohepatitis.

Figure 1

Mechanisms of intrahepatic glucose and lipid homeostasis leading to lipotoxicity and cell death. Intrahepatic free fatty acids are key to the development of NASH. Dietary fat is stored in adipocytes as triglycerides. They undergo lipolysis, and the free fatty acids are taken up into the liver. The two major fates of free fatty acids are to undergo beta oxidation in the mitochondria, or re‐esterification to triglycerides, where they are stored as lipid droplets or repackaged and excreted as VLDL. The triglycerides on lipid droplets can undergo lipolysis to form free fatty acids. When these two disposal pathways get overwhelmed, lipotoxic lipids form. This leads to oxidative stress, ER stress and recruitment of pro‐apoptotic receptors. With prolonged ER stress, a dysfunctional UPR occurs. Either DAMPs from breakdown products, or PAMPs from bacterial products can activate the inflammasome. All of these can lead to activation of caspases, which in turn lead to cell death. In boxes are key mediators of some of the processes, and in red are the pathogenic processes leading to cell death. ACC, acetyl Co‐A carboxylase; CHOP, CAATT enhancer binding homologous protein; CPT‐1, carnitine palmitoyltransferase 1; DAMP, danger‐associated molecular patterns; DNL, de novo lipogenesis; DR5, death receptor 5; ER, endoplasmic reticulum; FABP‐1, fatty acid binding protein‐1; FASN, fatty acid synthetase; FAT/CD36, fatty acid translocase/CD36; FATP5, fatty acid transport protein 5; JNK, c‐Jun N‐terminal kinase; MPC, mitochondrial pyruvate carrier; NASH, nonalcoholic steatohepatitis; PAMP, pathogen‐associated molecular proteins; SCD, stearoyl CoA‐desaturase; SREBP‐1c, sterol regulatory element binding protein‐1c; TCA, tricarboxylic acid; UPR, unfolded protein response; VLDL, very low‐density lipoprotein

Figure 2

Mechanism of action of drugs currently in phase‐II and phase‐III development. ACC, acetyl Co‐A carboxylase; ACL, adenosine triphosphate‐citrate lyase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CCR, C‐C motif chemokine receptor; CVC, cenicriviroc; DGAT2, diacylglycerol O‐acyltransferase 2; FASN, fatty acid synthase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; G3P, glycerol‐3‐phosphate; GGT, gamma‐glutamyl transpeptidase; GLP‐1, glucagon‐like peptide‐1; MoGAT2, monoacylglycerol O‐acyltransferase 2; MRE, magnetic resonance elastography; MRI‐PDFF, magnetic resonance imaging proton density fat fraction; NASH, nonalcoholic steatohepatitis; OCA, obeticholic acid; PPAR, peroxisome proliferator‐activated receptor; SCD1, stearoyl‐CoA desaturase 1; TG, triglyceride; thyroid hormone rep., thyroid hormone receptor