**6. Other Factors in NAFLD and NASH**

Most recently, first reports described that exosomes carrying a variety of cargoes, including proteins, fats, and various kinds of nucleic acids (mRNAs, microRNAs, other noncoding RNAs) have fundamental implications in liver pathobiology [141–144]. Although the precise mechanisms by which they contribute to NAFLD and NASH are still somewhat enigmatic, there are first reports proposing defined exosomal microRNAs such as miR-192 released from injured hepatocytes as potential new biomarkers to evaluate the progression from simple steatosis to NASH [145]. First encouraging studies have generated significant interest in exosomes as targets for biomarkers development [144].

Other researchers focus on potential roles of the adipose tissue in NAFLD. In particular, adipose tissue macrophages were proposed as key players in NAFLD [146]. There is a general consensus that a large set of signaling molecules such as lipids, microRNAs, adipokines and immune-related compounds are released from adipose tissue into the portal vein triggering hepatic inflammation [146]. In particular, the release of fatty acids from dysfunctional adipocytes results in liver parenchymal cell toxicity, which causes the ectopic accumulation of triglyceride-derived toxic metabolites increasing the activity of inflammatory pathways [147]. However, all these mechanisms are presently only partially understood and the impact of different macrophage phenotypes on the formation of NAFLD and NASH needs additional studies.

Another recent focus discussed in NAFLD and NASH research is the occurrence of quantitative and qualitative changes of the intestinal flora. Such a dysbiosis can result from altered food metabolism, intoxication, or increased permeability of the intestinal barrier. There is nowadays increasing evidence suggesting a critical role for the gut microbiome in the pathogenesis of obesity and metabolic syndrome [148]. The gut microbiota contributes to liver steatosis by modulating the uptake, bio-processing, fermentation, and synthesis of several effector molecules such as short-chain fatty acids, bile acids, cholines, and many other substances [149]. Moreover, it is intensively discussed at present if the microbiome composition can be used as a biomarker to differentiate between NAFLD and NASH [148]. However, standardized test systems or microbiota-targeted personalized treatment approaches for NAFLD and NASH are still not available.
