Table 1.
Summary of the pathways representing possible targets for the treatment of NASH
| Pathway | Comments |
|---|---|
| Insulin resistance | Clinical studies show effectiveness on steatosis and inflammation, but little effects on fibrosis |
| Lipid accumulation | Evidence from experimental models suggests that NASH actually worsens if triglyceride accumulation is blocked. Lipases regulating intracellular lipid trafficking (e.g. ATGL) are an interesting target but little data are available. |
| Inflammation: macrophages | M1 macrophage accumulation is a key event in both the adipose tissue and the liver. Possible targets include chemokines (e.g. CCL2), their receptors, cytokines released by these cells (TNF, IL-6), and osteopontin. Increased M2 polarization of macrophages to generate anti-inflammatory signals. Consider possible detrimental effects on fibrosis? |
| Inflammation: lymphocytes | Increase in regulatory T cell function or number. |
| Inflammation: inflammasomes | IL-1beta is released by inflammasome activation and drives inflammation and fibrosis. However, Activation of inflammasome in the gut may be protective on NASH by modulating the microbiota. |
| Inflammation: signaling pathways | NF-kappaB has pleiotropic effects and prevents of cell death. Targeting selective downstream targets of NF-kappa B would be more realistic |
| Renin-angiotensin system | Relevant for insulin resistance, liver inflammation and fibrosis. Well known drugs in clinical practice for decades. |
| Microbiome | Prebiotics, probiotics, antibiotics. |
| TLRs | Strong evidence as mediators of inflammation and fibrosis. However, targeting TLR may increase susceptibility to infections. |
| Modulation of the GLP-1 system | Long-acting GLP-1 ligands or DPP4 inhibitors. |
| JNK | Involved in insulin resistance and cell death. However, possible risk of hepatocarcinogenesis upon prolonged inhibition |
| Oxidative stress | Clinical studies have shown efficacy of vitamin E on inflammation but not fibrosis. Need for new, more active molecules. |
| Autophagy | Antisteatogenic effects but drives fibrogenesis. |
| ER stress | Involved in both insulin resistance and liver damage |
| Omega-3 | Possible effects on steatosis. Beneficial action on inflammation and fibrosis still controversial. |
| Adipokines | Increase in adiponectin levels or signaling, e.g. AMPK, has potential to limit metabolic abnormalities, liver inflammation and fibrosis. |
| Cannabinoids | Upcoming availability of peripheral-restricted antagonists |