Non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. As the burden of hepatitis C abates over the next decade, non-alcoholic fatty liver disease will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation. This overview briefly summarizes the most recent data on the pathophysiology, diagnosis, and treatment of non-alcoholic fatty liver disease. Ongoing clinical trials are focused on an array of disease mechanisms and reviewed here are how these treatments fit into the current paradigm of substrate overload lipotoxic liver injury. Many of the approaches are directed at downstream events such as inflammation, injury and fibrogenesis. Addressing more proximal processes such as dysfunctional satiety mechanisms and inappropriately parsimonious energy dissipation are potential therapeutic opportunities that if successfully understood and exploited would not only address fatty liver disease but also the other components of the metabolic syndrome such as obesity, diabetes and dyslipidemia.

Keywords: De novo lipogenesis; Fatty acids; Fibrogenesis; Insulin resistance; Lipotoxicity; Non-alcoholic steatohepatitis.

Fig. 1

Substrate overload lipotoxic injury (SOLLI) model of NASH pathogenesis. The primary metabolic substrates are the monosaccharides glucose and fructose that are turned into fatty acids in the liver and fatty acids themselves that are delivered to the liver from adipose tissue. From this perspective, the most proximal abnormalities in the pathogenesis of NASH are the supply of excess dietary carbohydrates and fatty acids. The carbohydrates are derived from dietary intake and the fatty acids primary from adipose tissue, especially in the setting of insulin resistance. Carbohydrates can be converted to fatty acids through the multi-enzymes process of de novo lipogenesis and the transcription factor SREBP1c plays a dominant role in regulating the expression of these enzymes. Fatty acids in the liver can be oxidized by mitochondria or converted back into triglyceride for export into the blood as VLDL. In the setting of carbohydrate and fatty acid substrate overload or impairment of the pathways of fatty acid disposal, or perhaps most likely a combination of both arms, fatty acids may promote the generation of lipotoxic species (e.g., diacylglycerols [DAGs], ceramides, lysophosphatidyl choline species [LPCs]) that mediate endoplasmic reticulum stress, mitochondrial dysfunction, hepatocellular injury, inflammation, and apoptosis to produce the histological phenotype currently called NASH. These processes are then the stimuli for fibrogenesis and possibly malignant transformation. Major modulators of the hepatocellular response to lipotoxic stress may include the gut microbiome, a variety of cytokines, chemokines, and adipokines, free cholesterol, uric acid, free cholesterol and possibly periodic hypoxia caused by obstructive sleep apnea (OSA). DNL, de novo lipogenesis; SREBP1c, sterol response element binding protein-1c; ACC, acetyl-Coenzyme A carboxylase; FAS, fatty acid synthetase; SCD, stearoyl-Coenzyme A desaturase; CYP, cytochrome P450; PNPLA3, patatin like phospholipase domain containing 3; VLDL, very low density lipoprotein; OSA, obstructive sleep apnea; HCC, hepatocellular carcinoma

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)