*Hepatic Lipid Homeostasis in NAFLD DOI: http://dx.doi.org/10.5772/intechopen.108168*

### **Figure 1.**

*Hepatic lipid metabolism. The homeostasis of intrahepatic lipid is governed by the four major pathways. Fatty acids (FAs), derived from blood circulation or de novo lipogenesis, can be stored in the form of lipid droplets (LDs). Conversely, FAs could be oxidized into acetyl-CoA as a substrate of ketone bodies, cholesterol, or glucose. FAs can also be esterified into triglyceride, which could form very low-density lipoprotein (VLDL) via apolipoprotein (Apo) B100 and microsomal TG transfer protein (MTTP) and further excreted from the liver.*

sugar-enriched diet, diet enriched in saturated fat was associated with higher adipose tissue lipolysis [18].

Once flow to the hepatic vein, FAs are transported across the plasma membrane, mainly *via* transporter-mediated mechanisms, which is predominately mediated by fatty acid transport proteins (FATP), fatty acid translocase (FAT), also referred to as cluster of differentiation 36 (CD36), and caveolins located in the hepatocyte plasma membrane [19]. Studies found that the knockdown of FATP2 or FATP5, FATP isoforms primarily in the liver, reduces hepatocyte FAs uptake and further reverses steatosis [20, 21], indicating the FATP-mediated facilitation of steatosis. For CD36, it is regulated by peroxisome proliferator-activated receptor (PPAR) γ, pregnane X receptor, and liver X receptor (LXR) to facilitate long-chain FAs transportation. Studies identified that high-fat diet (HFD) upregulates mRNA and protein expression of CD36 and further aggravates hepatic steatosis, while liver-specific knockout of CD36 downregulates hepatic lipid levels and improves insulin resistance [22, 23]. CD36 is located in the hepatocyte plasma membrane in steatosis and NASH, while the expression of which is week in cytoplasm of hepatocytes in normal livers, which may indicate that the translocation of CD36 protein from cytoplasm to membrane could induce NAFLD progression (**Figure 2**) [24]. Caveolins are the third kind of transport-mediated protein, of which caveolin 1 is increased and mainly located in the centrilobular zone 3, the most severe part of

steatosis in the liver with NAFLD. Study found that the upregulation of caveolin 1 might have clinical benefits in alleviating lipid accumulation in NAFLD [25, 26].

When uptake into cytoplasm, this hydrophobic FAs is binded with fatty acidbinding proteins (FABP) 1, the predominant isoform in the liver, to shuttle between different organelles. FABP1 could bind with cytotoxic-free FAs and promote its

### **Figure 2.**

*Hepatic lipid metabolism in NAFLD. In NAFLD, cluster of differentiation 36 (CD36), fatty acid transport protein (FATP)-2 and -5 mediates uptake of circulating lipids increases. Fatty acid binding protein (FABP) 1 is increased in the early stage of disease and may decline with disease progression, which lead to lipotoxicity deterioration and disease progression. As for de novo lipogenesis, elevated sterol regulatory element-binding protein 1c (SREBP1c) and declined carbohydrate regulatory element-binding protein (ChREBP) enhance the downstream expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) in NAFLD. For lipid disposal, mitochondrial dysfunction may lead to increased generation of reactive oxygen species (ROS) and utilization of cytochrome- and peroxisome-mediated oxidation. Meanwhile, lipid export compensates for increased hepatic triglyceride levels in the early stage of disease. While the levels of microsomal triglyceride transfer protein (MTTP) and apolipoprotein B100 (ApoB100) may be decreased, therefore limiting very low density lipoprotein (VLDL) export and facilitating lipid accumulation in NASH. Green arrow: Increased expression. Red arrow: Decreased expression. PPAR, peroxisome proliferator-activated receptor.*

oxidation and incorporation into TG, protecting the effect of lipotoxicity. In stage of steatosis, overexpression of FABP1 protein might enhance lipid flux to compensate lipotoxicity. While in the mid or late stage of NAFLD, presented as mild or advanced fibrosis, the level of FABP1 protein undergoes a series of decline, which leads to lipotoxicity deterioration and disease progression [27, 28].
