Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal

Abstract

Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children in the USA and many other parts of the world. NAFLD encompasses a wide spectrum of conditions associated with the overaccumulation of lipids in the liver, ranging from steatosis to nonalcoholic steatohepatitis, to cirrhosis and its feared complications of portal hypertension, liver failure and hepatocellular carcinoma. In this article, we will focus on the growing evidence linking changes in hepatic lipid metabolism and accumulation of specific lipid types in the liver with hepatocellular damage, inflammation and apoptosis, resulting in disease progression to the more serious forms of this condition.

Figure 1. Potential Mechanisms of Hepatic Steatosis in NAFLD

A net retention of fat in hepatocytes could potentially result from alterations in the (1) uptake, (2) de novo synthesis in the liver itself, (3) oxidation, and (4) export pathways of hepatic lipid homeostasis. The type and number of processes involve may potentially play an important role in whether the disease follows a benign non-progressive clinical course, or a progressive one evolving into NASH and NASH-cirrhosis. Abbreviations: FFA, free fatty acids; TG, triglycerides; ApoB, apolipoprotein B; HSL, hormone sensitive lipase.

Figure 2. Hepatic lipid partitioning and liver damage in NAFLD

Hepatic steatosis characteristic of patients with NAFLD, which is commonly associated with obesity and insulin resistance results mainly from increase flow of free fatty acids from circulation. In this context, lipid compartmentation in liver cells and in particular the ratio of monounsaturated to saturated free fatty acids that is a function of SCD1 activity, plays a central role in whether adaptation occurs resulting in a benign clinical course, or there is ongoing hepatocellular apoptosis, and liver damage resulting in steatohepatitis and fibrosis development.. Abbreviations: SCD1, stearoyl-CoA desaturase-1.

Figure 3. Lipotoxicity pathways in NAFLD

FFA may activate several signaling pathways of apoptosis including up-regulation and increased number of death receptors such as Fas and TRAIL receptor 5 (DR5), at the level of the plasma membrane, lysosomal permeabilization, and ER stress both coupled to mitochondrial dysfunction resulting in activation of the mitochondrial pathway of apoptosis. These toxic fatty acids may also activate TLR4 signaling resulting in up-regulation of several pro-inflammatory cytokines. Finally, other lipid types such as free cholesterol (FC) and ceramide may induce mitochondrial dysfunction and activate the mitochondrial pathway of apoptosis. Abbreviations: FFA, free fatty acids; SFA, saturated fatty acids; MUFA, monounsaturated fatty acids, FC, free cholesterol, CE, cholesteryl-ester; ER, endoplasmic reticulum.