Malhi, Harmeet

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

Circulating extracellular vesicles (EVs) are a novel and emerging biomarker for nonalcoholic steatohepatitis (NASH). It has been demonstrated that total circulating EVs and hepatocyte‐derived EVs are elevated in male mice with diet‐induced NASH. How hepatocyte‐derived EVs change over time and other cellular sources of EVs in NASH have not been determined. Our objective was to define the quantitative evolution of hepatocyte‐derived, macrophage‐derived, neutrophil‐derived, and platelet‐derived EVs in male and female mice with dietary NASH. Fluorescently labeled antibodies and a nanoscale flow cytometer were used to detect plasma levels of EVs. Asialoglycoprotein receptor 1 (ASGR1) and cytochrome P450 family 2 subfamily E member 1 (CYP2E1) are markers of hepatocyte‐derived EVs; galectin 3 is a marker of macrophage‐derived EVs; common epitope on lymphocyte antigen 6 complex, locus G/C1 (Ly‐6G and Ly‐6C) is a marker of neutrophil‐derived EVs; and clusters of differentiation 61 (CD61) is a marker of platelet‐derived EVs. Nonalcoholic fatty liver disease activity score (NAS) was calculated using hematoxylin and eosin‐stained liver sections, and magnetic resonance imaging (MRI) was used for measurement of the fat fraction and elastography. Hepatocyte‐derived EVs increased in both male and female mice at 12 and 10 weeks of feeding, respectively, and remained elevated at 24 weeks in both male and female mice and at 48 weeks in male mice and 36 weeks in female mice. Macrophage‐ and neutrophil‐derived EVs were significantly elevated at 24 weeks of dietary feeding concomitant with the histologic presence of inflammatory foci in the liver. In fat‐, fructose‐, and cholesterol‐ (FFC) fed male mice, platelet‐derived EVs were elevated at 12, 24, and 48 weeks, whereas in female mice, platelet derived EVs were significantly elevated at 24 weeks. Hepatocyte‐, macrophage‐ and neutrophil‐derived EVs correlated well with the histologic NAS. Conclusion: Circulating cell‐type‐specific EVs may be a novel biomarker for NASH diagnosis and longitudinal follow up.

AbstractEndoplasmic reticulum (ER) stress is a major contributor to liver disease and hepatic fibrosis, but the role it plays varies depending on the cause and progression of the disease. Furthermore, ER stress plays a distinct role in hepatocytes versus hepatic stellate cells (HSCs), which adds to the complexity of understanding ER stress and its downstream signaling through the unfolded protein response (UPR) in liver disease. Here, the authors focus on the current literature of ER stress in nonalcoholic and alcoholic fatty liver diseases, how ER stress impacts hepatocyte injury, and the role of ER stress in HSC activation and hepatic fibrosis. This review provides insight into the complex signaling and regulation of the UPR, parallels and distinctions between different liver diseases, and how ER stress may be targeted as an antisteatotic or antifibrotic therapy to limit the progression of liver disease.