Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

Regression of Hepatic Fibrosis and Evolution of Cirrhosis: A Concise Review

“… 81 Inflammation in non alcoholic steatohepatitis is “metabolic” in nature 82 ; several pathways including insulin resistance, lipotoxicity, lipid peroxidation, and necroinflammation precipitate steatohepatitis. 83 With regression of fibrosis, most of the risk factors for development of HCC persist in NAFLD; lipid metabolic reprogramming involving carnitine palmitoyl transferase and fatty acid β-oxidation, being key mechanisms. 84 Similarly, the risk of HCC persists in cirrhosis secondary to hemochromatosis even after “clinically successful” therapeutic phlebotomies.…”

Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System

“…As DAMPs can initiate an inflammatory process without the participation of infective agents, they are actors of a sterile inflammation. More precisely, the inflammatory response which occurs in NAFLD is due to metabolic alterations, such as insulin resistance, excess of fat, and lipotoxicity, therefore it can be called “metabolic inflammation.” This process is characterized by a chronic low-grade immune activation, which does not resolve ( 148 ). This contrasts with an acute insult like microbial infection, in which the immune response is strong, limited in time, and has the purpose of eliminating the pathogen and making the person survive.…”

“…Natural killer T (NKT) cells are CD1d restricted lymphocytes, which recognize lipid antigens. This definition is due to their expression of both the classic T lymphocyte (CD3) and natural killer cell markers (e.g., CD56) ( 148 ). These cells can be divided into two subtypes: invariant NKT (iNKT), or NKT type 1, which possess a semi-invariant TCR-α chain (which in humans includes the Vα24/Jα18 region), and type 2, non-invariant NKT (type 2), with a more variable TCR.…”

The role of NK cells in oncolytic viral therapy: a focus on hepatocellular carcinoma

“…Chronic HBV infection is the leading cause of HCC in most African countries, whilst in North America and Europe, HCV is the most frequent virus-related cause of HCC development [ 59 ] . NAFLD, with a prevalence of approximately 25% globally, is the most common liver disease and represents a significant risk factor for HCC comprising 10%-20% of cases in the United States [ 60 , 61 ] . Independent of NAFLD, features of the metabolic syndrome such as obesity and diabetes mellitus confer increased HCC risk [ 62 , 63 ] .…”