Potential conflict of interest: K.W. has nothing to report. A.M.D. reports receiving consulting fees from Pfizer, Novartis, and Lumena, participating in clinical trials with Gilead Sciences, Conatus, Galmed, NGM Biopharmaceuticals, Bristol Myers Squibb, Madrigal, Galectin Therapeutics, Exalenz Biosciences, Shire, Intercept, and Genfit, receiving grant support from and participating in clinical trials with Immuron, receiving grant support from Metabolon and Prometheus, receiving consulting fees from and participating in a clinical trial with Boehringer Ingelheim, receiving honoraria from and participating in a clinical trial with Allergan, receiving consulting fees and grant support for a research collaboration from Celgene, and holding a pending patent application for “Development of Novel Therapeutics to Treat Non‐Alcoholic Steatohepatitis (NASH).” No other potential conflict of interest relevant to this article was reported. C.A.M. receives grant support through participating in clinical trials with Gilead Sciences, Conatus, Galmed, NGM Biopharmaceuticals, Bristol Myers Squibb, Madrigal, Galectin Therapeutics, Exalenz Biosciences, Shire, Intercept, Immuron, Intercept, Allergan, Boehringer Ingelheim, TaiwainJ Pharmaceuticals, and Genfit. No other potential conflict of interest relevant to this article was reported.
A Complex Disease, Distilled Into Four Processes
Nonalcoholic steatohepatitis (NASH) is a complex disease involving many molecular pathways and numerous genetic, epigenetic, and environmental contributors. Because NASH causes more liver damage than simple steatosis (fat), stopping the chain of events driving steatosis to NASH has been a focus in the field.1 This review will explain key mechanisms thought to cause NASH, discuss potential molecular targets, and review approved and experimental therapies for NASH. NASH involves four interconnected processes: (1) deranged lipid metabolism, (2) cell death, (3) inflammation, and (4) wound healing. The goal is to simplify the interplay between these processes to provide a framework for understanding the molecular basis of NASH (Fig. 1).
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Figure 1: Current and emerging therapies for NASH. Multiple molecular pathways are involved in NASH pathogenesis Anti‐NASH strategies are shown according to their mechanism of action. Green color indicates agonist; red color indicates antagonist. Abbreviations: CTGF, connective tissue growth factor; FGF19, fibrosis growth factor 19; IBAT, ileal bile acid transporter; LPS, lipopolysaccharide; PDE, phosphodiesterase.
Step 1: Deranged Lipid Metabolism
Abnormal accumulation of lipids in hepatocytes is an essential aspect of NASH.3 These lipids derive from the systemic circulation, de novo synthesis, and reduced degradation or export from hepatocytes. Storing lipids as triglycerides is not directly hepatotoxic and seems to protect against NASH, whereas diacyl glycerols, cholesterol, phosphatidylcholines, and certain saturated fatty acids (FAs) are particularly toxic.4 Because lipotoxicity promotes cell death and inflammation, many interventions target toxic lipid buildup. Some have been successful, whereas others have not. For example, stearoyl‐coenzyme A desaturase converts saturated FA into less hepatotoxic, monounsaturated FA. Aramchol targets this enzyme and reduces hepatic fat content in NASH.5 Polyunsaturated FAs may be protective against NASH. However, ethyl‐eicosapentaenoic acid (EPA‐E) had no effect on NASH histology.6 Two drugs effectively reduced hepatic fat at 12 weeks in phase II trials. These include GS‐0976, an inhibitor of acetyl‐CoA carboxylase, which catalyzes the first step in hepatic lipid synthesis,7 and MGL‐3196, a liver‐specific thyroid hormone receptor β (THRβ) agonist that downregulates hepatic lipid synthesis.8
Obesity and insulin resistance create metabolic stress, another key factor in lipotoxicity. Insulin reduces FA release from adipocytes. Because insulin resistance can overwhelm the liver with adipose‐derived FA, diabetes treatments are potential therapies for NASH. Pioglitazone, a peroxisome proliferator‐activated receptor (PPAR) γ agonist, improved NASH but has side effects such as weight gain.9 Elafibranor, a PPAR αδ agonist, tended to improve NASH in one study.11 MSDC‐0602K, a PPARγ‐sparing drug that may have fewer side effects than current PPARγ agonists, is currently under study for NASH.12 Metformin did not improve NASH despite promoting weight loss and insulin sensitization.13 The glucagon‐like peptide 1 (GLP‐1) analogue liraglutide improved NASH but worsened liver fibrosis.14
Bile acids (BAs) contribute to NASH pathogenesis by facilitating dietary fat absorption and acting as hormones. After conjugation by small‐intestinal bacteria, secondary BAs are absorbed into the systemic circulation and bind to farnesoid X receptor (FXR) and other receptors to regulate tissue insulin sensitivity and lipid synthesis. Hence BA metabolism is a potential NASH therapeutic target. NGM282, a fibroblast growth factor 19 (FGF‐19) variant, regulates BA synthesis and reduced hepatic steatosis and aminotransferases in a recently completed phase II trial.15 Volixibat, an inhibitor of the ileal BA transporter, is currently in a phase II trial.16 The gut microbiome affects circulation of BAs, and the antibiotic solithromycin improved NASH in a pilot study.17 Several FXR agonists are under study alone or in combination. One such drug, obeticholic acid, improved fibrosis and NASH in a large phase II study and is now in phase III.18
Step 2: Cell Death
Once hepatocytes are injured by the toxic buildup of lipids, oxidative and endoplasmic reticulum stress pathways trigger cell death. Downstream mediators of these pathways try to reestablish tissue homeostasis by initiating repair responses. The balance between injury and repair determines whether NASH progresses or resolves. Repetitive injury and/or dysregulated repair promote neoplasia of repair‐related cells, progressive scarring, and increased risk for liver cancer and cirrhosis. Caspases, key regulators of cell death, have been studied as NASH treatments. Emricasan, a pan‐caspase inhibitor, improved portal hypertension in a phase IIa study and is now being evaluated to assess its impact on fibrosis.19 Apoptosis‐related kinase‐1 (ASK‐1) is an ASK that is activated by oxidative stress. Selonsertib, an ASK‐1 inhibitor, reduced fibrosis in a small phase II study and is now under investigation for NASH with advanced fibrosis.20 A phase II study demonstrated that GR‐MD‐02, an inhibitor of the profibrogenic factor, Galectin‐3, did not overtly improve advanced fibrosis despite reducing portal pressure in some patients with NASH. This agent is currently moving into phase III trials.21 Finally, an antioxidant vitamin, vitamin E, improved NASH in patients without diabetes.10
Step 3: Inflammation
Inflammation is necessary to repair liver injury, but recovery depends on the type and number of inflammatory cells that accumulate. Diet, adiposity, metabolic syndrome, and the intestinal microbiome modulate the inflammatory response.22 The gut innate immune system is critically involved in NASH pathogenesis because it regulates trafficking of bacteria and bacterial products through the portal circulation. Endotoxin, or lipopolysaccharide (LPS), is a key proinflammatory molecule. Anti‐LPS antibodies contained in hyperimmune bovine colostrum (IMM124E) impact inflammation and insulin resistance and are being studied in NASH.23 Toll‐like receptors (TLRs) recognize LPS, and JKB‐121, an inhibitor of TLR‐4, is also being evaluated.24 Chemokines that direct inflammation are also promising therapeutic targets. Cenicriviroc, an antagonist of the chemokine receptors (CCRs), CCR2/CCR5, did not improve NASH but seemed to reduce liver fibrosis and is now in phase III study.25 Tipelukast, an anti‐inflammatory agent that inhibits leukotriene production, is being studied in pulmonary fibrosis and NASH.26
Step 4: Fibrosis
Cirrhosis, the most deleterious consequence of NASH, occurs because regenerative responses cannot keep pace with hepatocyte death, and thus perpetuate futile wound‐healing responses that drive neoplasia and fibrosis. These defective regenerative efforts also promote liver cancer. Hepatic stellate cells (HSCs) are the major producers of fibrous matrix in liver.27 Thus, mediators of HSC activation, such as transforming growth factor β (TGF‐β), are important therapeutic targets. Fresolimumab, a monoclonal antibody against TGF‐β, is under study for idiopathic pulmonary fibrosis (IPF) and cancer but has not yet been tested in NASH.28 Pamrevlumab, a monoclonal antibody against the TGF‐β's target gene connective tissue growth factor (CTGF), improved IPF and may soon be studied in NASH. Simtuzumab, a monoclonal antibody against lysyl oxidase homolog 2 (LOXL2), a collagen crosslinking enzyme, was ineffective in both IPF and NASH.20 ND‐L02‐s0201, which targets heat shock protein 47, a factor essential for maturation and secretion of collagen, is entering clinical trials.29
NASH: New Approaches to Save Hepatocytes
Numerous molecular pathways interact to orchestrate the pathogenesis of NASH. Although many new drugs and molecular targets appear promising, there are not yet FDA‐approved drugs for NASH. Drug development has focused on biologically plausible, single‐molecule targets. However, the disappointing results of recent clinical trials suggest that this strategy is unlikely to improve a disease with such a complex pathogenesis. Blocking pathways that drive fibrosis progression in NASH will also be essential, although difficult, because fibrosis severity determines clinical outcomes. Thus, new interventions and novel approaches are necessary. Treatments may need to be individualized to patients' genetic risk variants or personalized to metabolic/environmental stressors, as is currently being done in cancer therapeutics. Ideally, disease‐modifying factors will eventually be identified with blood tests, permitting stratification of the heterogeneous population of patients with NASH into more homogeneous subgroups for optimal treatment.
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