Inflammatory and fibrotic mechanisms in NAFLD-Implications for new treatment strategies

Abstract

Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.

Keywords: fibrosis; insulin resistance; lipotoxicity; liver cancer; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

Figure 1.. Pathogenesis of NAFLD – inflammatory and fibrogenic signaling events.

NASH is the hepatic manifestation of the metabolic syndrome. Adipose tissue inflammation and insulin resistance leads to hepatic overload with fatty acids and glucose driving hepatic steatosis, ER stress and activation of the unfolded protein response leading to inflammasome activation and cell death. Adipokines and gut microbiome derived bacterial products modulate hepatic inflammation and nuclear receptor signaling (FXR, LXR, PXR and Vitamin D receptor) but may also directly activate hepatic stellate cells. Hepatocyte injury signals lead to activation of hepatic stellate cells and inflammatory cells converging on hepatic fibrogenesis. Emerging pathways and intracellular signaling molecules may enable novel strategies for therapeutic intervention as are new techniques such as engineered T cells to kill activated stellate cells or HSC-targeted chemically engineered antifibrotic drugs. HSC, hepatic stellate cells. Modified from [161]