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Review
. 2016 Aug;65(8):1049-61.
doi: 10.1016/j.metabol.2016.02.014. Epub 2016 Mar 3.

Molecular Mechanisms of Lipotoxicity and Glucotoxicity in Nonalcoholic Fatty Liver Disease

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Free PMC article
Review

Molecular Mechanisms of Lipotoxicity and Glucotoxicity in Nonalcoholic Fatty Liver Disease

Manoela Mota et al. Metabolism. .
Free PMC article

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.

Keywords: CHOP; JNK; Lipid; NASH; Oxidative stress.

Figures

Figure 1
Figure 1. Molecular mechanisms of hepatocyte lipotoxicity and glutotoxicity
Insulin resistance, a hallmark of NAFLD, leads to an increase in serum concentration of circulating FFAs. FFAs are transported into the hepatocyte where they can be esterified into neutral triglycerides resulting in hepatic steatosis. Esterification of FFAs represents a buffering mechanism allowing cells to maintain viability in the face of excess non-esterified FFAs exposure. Saturated FFAs (sFFA) in excess are toxic to liver cells and they can accumulate in the endoplasmic reticulum (ER) and induce an ER stress, which in turn induce the transcription factor CHOP and induce JNK activity. Other hepatotoxic lipids such as palmitate (PA)-derived lysophosphatidyl choline (LPC) also mediate JNK-dependent hepatic toxicity downstream of glycogen synthase kinase (GSK)-3 signaling cascades and ER stress induction. Active JNK phosphorylates the transcription factor c-Jun, which cooperates with CHOP to upregulate the transcription of the pro-apoptotic BH3-only protein PUMA. CHOP also mediate the upregulation of another BH3-only protein BIM; and BIM and PUMA cooperate in activating the executioner proapoptotic protein Bax, causing mitochondrial dysfunction, activation of the effector caspases 3/7 and cellular apoptosis. CHOP also upregulates the expression of the death receptor DR5, resulting in increased DR5 cell surface expression which clustering of the receptor leading to recruitment and activation of the executioner caspase-8, which ultimately induces Bax. Saturated FFAs-induced mitochondrial dysfunctions is also mediated by a Bax-dependent permeabilization of lysosomes and release of cathepsin B in the cytosol. Mitochondrial dysfunction also results in generation of reactive oxygen species (ROS) which further induce cellular demise. In addition, excess dietary sugars, resulting in chronic hyperglycemia, can further induce liver toxicity or glucotoxicity by increasing hepatic steatosis via de novo lipogenesis (DNL) and exacerbating insulin resistance and cellular demise, through the activation of oxidative and ER stress responses, and/or downstream the modulation of the activity of AMP-activated protein kinase (AMPK) and protein-tyrosine phosphatase 1B (PTP1B). Also, chronic hyperinsulinemia is associated with hepatic steatosis via the upregulation of hepatic lipogenic gene expression (ACC, FAS, SCD-1).

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