Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

Abstract

Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

Keywords: Liver fibrosis; clinical trials; inflammation; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); steatosis.

Figure 1

Clinical conditions from normal liver to NAFLD, NASH, cirrhosis, and HCC. About 25% of the general population have NAFLD, of which a substantial fraction (10–30%) is at risk for progressing towards relevant fibrosis. Between 0.3–3% of patients with fibrosis progress to cirrhosis and/or HCC per year. The pathogenesis is influenced by many factors including genetic factors, age, diabetes, obesity, alcohol, and lifestyle. Weight loss, physical exercise, consumption of coffee, Mediterranean diet, and a vegetable-rich diet have positive effects on disease outcome and are recommended to prevent NAFLD progression. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; HCC, hepatocellular carcinoma.

Figure 2

Therapeutic targets in liver fibrosis. The understanding of molecular processes leading to hepatic fibrosis offers emerging therapeutic targets for preventing fibrosis and enhancing therapy. Effective drugs are beneficial to prevent cell death, inflammation, and reactive oxygen species formation. Other drugs target hepatic fat metabolism, the gut-liver axis, and matrix expression or turnover. The figure is based on (34). ACC, acetyl-CoA carboxylase; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FGF, fibroblast growth factor; FFA, free fatty acids; FXR, farnesoid X receptor; PPAR, peroxisome proliferator- activated receptor; ROS, reactive oxygen species; SHP, small heterodimer partner; SREBP1, Sterol regulatory element binding protein-1; TGR5, G protein-coupled bile acid receptor 1 (GPBAR1); THRβ, thyroid hormone receptor-β; TNF, tumor necrosis factor.