Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

Abstract

The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

“…ER stress has been observed both in liver samples from patients with NAFLD and experimental models of fatty liver 1 2 29. Importantly, chronic ER stress is linked to lipid metabolism dysregulation and fatty liver disease progression 1 2 30.…”

“…Importantly, chronic ER stress is linked to lipid metabolism dysregulation and fatty liver disease progression 1 2 30. In view of this, we examined the expression of key ER stress response genes in the livers of Fgf15 +/+ and Fgf15 −/− mice fed control or HFD for 12 weeks.…”

“…However, TG accumulation per se is not thought to mediate hepatocellular damage, being considered as an adaptive protective response to cope with the increased flux of free fatty acids (FFA) within the liver 1. In patients with NAFLD, accumulating hepatic FFAs come from different sources, including the adipose tissue where insulin resistance promotes lipolysis, from de novo lipogenesis and from the diet 1 2. Peripheral insulin resistance leads to a compensatory hyperinsulinemia, which further drives hepatic de novo lipogenesis.…”

Metabolic risk factors are associated with non‐hepatitis B non‐hepatitis C hepatocellular carcinoma in Taiwan, an endemic area of chronic hepatitis B

“…These results suggest that fatty change in tissue may be pathognomonic and play some role in the hepatocarcinogenesis of nonviral HCC. In their study of the mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease, Mota et al41 described the involvement of the cytokine pathway and caspase activation and identified the common denominator as metabolic derangement, such as glucose intolerance and insulin resistance in tissue. The potential link between those cytokine pathways and hepatocarcinogenesis warrants further investigation.…”

Lipid Metabolism in Liver Cancer

“…First, chronic inflammation, the increased release of adipokine, and insulin resistance may affect cell proliferation and responsiveness [42,43]. Second, enhanced lipogenesis and fat deposition may induce extensive lipotoxicity, oxidative stress, and subsequent DNA damages [44,45]. Third, oncogenic insulin-like growth factor (IGF)-1/PI3K/mTOR, tumor necrosis factor (TNF)-alpha/mitogen-activated protein kinase (MAPK), and/or interleukin (IL)-6/STAT3 pathways were actively involved in HCC [46,47].…”