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