Fig. 2

The SOLLI model predicts targets of therapy. Shown are many of the agents that have been studied in recent clinical trials or are the subject of ongoing trials. Healthy eating habits and bariatric surgery regulate the intake of metabolic substrates and thus their reduction is a treatment approach targeting the most proximal events in the process. Pharmacologic manipulation of eating behaviors and satiety may also be effective proximal interventions. Adipose tissue insulin resistance allows inappropriate lipolysis and release of fatty acids into the circulation which can be taken up by the liver. Both fatty acids and glucose in the blood can be diverted to oxidative pathways (green arrows) in other tissues and these pathways are thought to be augmented by exercise, PPARγ and PPARδ ligands, GLP-1 analogues, and other hypothetical interventions under investigation. The synthesis of fatty acids in the liver, or de novo lipogenesis, can be down-regulated by decreasing the regulatory transcription factor SREBP1c or by inhibiting specific enzymes in the DNL pathway. Fatty acids in the liver can be used in a large number of metabolic pathways but for disposal, they are oxidized by mitochondria, peroxisomes, and certain cytochrome P450 isoforms (CYPs) or reesterified to glycerol to form triglyceride. Pharmacologic promotion of triglyceride formation would increase lipoprotein secretion into the blood as very low density lipoprotein (VLDL) and could thus increase the risk of cardiovascular disease--not a likely treatment approach for NASH. Little is known about the lipotoxic species generated in NASH, but once these are better characterized, specifically inhibiting their formation or accelerating their disposal could become effective treatment approaches. Many of the treatment approaches in current clinical trials are focused on managing the consequences of lipotoxic injury by using anti-inflammatory agents, anti-apoptotic agents and anti-fibrotics. (Red arrows indicate inhibitory approaches; green arrows indicate possible beneficial diversion of metabolic substrates)