| Free Fatty Acids (FFA)
|
Originates from adipose tissue with insulin resistant status, from de novo lipogenesis (from carbohydrates), luminal nutrients, decreased export as TG in very-low density lipoproteins (VLDL) Internalized by liver plasma membrane transporter CD36 (increased expression during insulin resistant status) Especially toxic: saturated FFA (e.g., palmitate, stearate); less toxic: monounsaturated FFA (e.g., oleate)
|
| Triglycerides (TG)
|
Originates from increased influx of FFAs in the liver and combination with one molecule of glycerol Accumulates as micro-, and macro-droplets At the early stage of NAFLD, TG represent a type of inert form protective against the ongoing lipotoxic injury [51,54]
|
| Lysophosphatidylcholine (LPC)
|
Originates from phosphatidylcholine (intracellular action of phospholipase A2 or from extracellular lecithin-cholesterol acyltransferase) Can mediate intracellular damage (endoplasmic reticulum stress, activation of apoptotic pathways downstream of JNK), also interacting with FFA palmitate [55,56]
|
| Ceramides
|
Originates from serine and palmitoyl-CoA (enzyme serine palmitoyltransferase) and from sphingomyelin (enzyme neutral sphingomyelinase) Can promote inflammation and cell toxicity via interaction with TNFα. Inhibition of ceramide synthesis decreases steatosis, cell injury, and insulin sensitivity in animal models of NAFLD [57] Mediates insulin resistance, cell toxicity, and pro-inflammatory effects (sequence IL-1 → ceramides → TNFα → inflammation) [57] Can induce release of extracellular vesicles (EV) → cell-cell communication (also in NASH)
|
| Free Cholesterol
|
Can originate via the following pathway: liver steatosis/NASH → increased expression sterol regulatory element-binding protein (SREBP)-2 → upregulation of HMGCoA reductase → increased synthesis of free cholesterol (mitochondria) [58] → apoptosis → JNK-dependent pro-inflammatory pathways Role in inflammation, fibrosis, and liver injury [59] Target cells: hepatocytes, stellate cells, and Kupffer cells
|
