Food components with antifibrotic activity and implications in prevention of liver disease

Abstract

Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.

Keywords: Antifibrotic food components; Hepatic stellate cells; Liver disease; Liver fibrosis; NAFLD.

Figure 1

Major events occurring in the hepatocyte during NAFLD development. Increases in the flux of free fatty acids from adipose tissue and lipogenesis via the activation of SREBP-1c and ChREBP pathways in the liver lead to TG accumulation (steatosis). Also, lipotoxic lipid intermediates are produced, which trigger ER stress, ROS generation, and inflammatory cytokine production, ultimately inducing hepatocyte apoptosis.

Figure 2

The effect of hepatocytes and macrophages on HSCs for ECM accumulation. Apoptic bodies of hepatocytes and other substances released from stressed and apoptotic hepatocytes, e.g., nucleotides, ROS, lipid peroxides, and inflammatory cytokines, stimulate macrophages and HSCs. Resident macrophages, i.e., Kupffer cells, and recruited macrophages (from Ly6C^high monocytes) are activated by the products of hepatocyte apoptosis, producing inflammatory cytokines and TGFβ. The inflammatory and fibrogenic cytokines activate SMAD3 and NFκB pathways in HSCs, leading to the activation, proliferation, and survival of HSCs. As a result, ECM production is increases while ECM breakdown is decreased.

Figure 3

Potential mechanisms of action for the anti-fibrotic actions of food components in vivo and in vitro. Food components in blue boxes have been shown to prevent liver fibrosis development in vivo; and those in green boxes have been shown to affect activation, inactivation and/or apoptosis of HSCs in vitro. Red lines indicate “inhibition” and blue arrow lines indicate “increase”.