**7. Diagnosis and management of NAFLD**

Liver biopsy is the gold standard to diagnose NAFLD. However, this procedure is invasive, expensive, and time-consuming, which limits its clinical application [89, 90]. MRI is highly sensitive and offers the possibility to quantitate fat tissue, which might be limited by high costs. Elastography could determine the elastic properties of liver; however, the thickness of peripheral tissue contributes as limiting factor. As for serological method, although ALT shows a low specificity for NAFLD, it still be the most common diagnostic biomarker. Besides, cytokeratin-18 (CK18) could be used to diagnose NASH. Lipidomics serves as a new method and could utilize the specific signature of various lipids to identify NAFLD, of which studies found that lysophospholipids (LPLs), TG, bis-(monoacylglycerol) phosphate (BMP), 5-, 8-, 11-hydroxyeicosatetraenoic acids (5-,8-,11-HETEs), 9-,13-hydroxyoctadecadienoic acids (9-,13-HODEs), and short- and medium-chain TG are elevated, while phosphoinositols (PI), phosphatidylethanolamines (PE), and phosphatidylcholines (PC) are reduced [91–94].

Decreasing the synthesis and/or increasing the disposal of intrahepatic FAs has been suggested to attenuate the risk of NAFLD. Lifestyle interventions composing of diet, exercise, and weight loss remain the optimal therapeutic strategy, of which general caloric restriction is one of the most effective ways to reduce liver FAs uptake. While, compared with general caloric restriction, studies indicated the additional metabolic benefits of intermittent fasting, including a reduction of hepatic steatosis, inflammation and PKCε activation, and increased insulin sensitivity [95, 96]. A meta-analysis found that people lose at least 5% of body weight could improve hepatic steatosis and lose at least 7% of body weight could improve NASH [97]. Therefore, caloric restriction and loss weight are the important measures to relieve NAFLD.

For patients failed to achieve lifestyle modification, pharmacological medication may be needed to reduce FAs accumulation. Several studies target to inhibit either ACC or DGAT2, which could reduce DNL and therefore lower the concentration of TG [98, 99]. Meanwhile, pathways associated with insulin resistance have been demonstrated as a therapeutic target of NAFLD, including bile acid-based insulin sensitization, peroxisome proliferator-activator receptors, FGF21, and metformin. Obeticholic acid (OCA), a selective farnesoid X receptor (FXR) agonist, is the first synthetic bile acid for the treatment of NASH that showed the potential anti-inflammatory and anti-fibrotic effects in the liver [100]. Thiazolidinedione, a selective ligand of the PPARs, seems to decrease IHTAG content [101]. Additionally, saroglitazar was demonstrated lowering steatosis and ALT in mouse with NASH [102]. Moreover, supplementation with n-3 polyunsaturated fatty acid (PUFA) could also reduce the concentration of TG [103].
