Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC

Abstract

Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.

Keywords: adipokines; hepatocellular carcinoma (HCC); hepatokines; non-alcholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); obesity; type 2 diabetes.

Figure 1

Type 2 diabetes and obesity aggravate the progression of NAFLD/NASH to HCC. Clinically, type 2 diabetes coexists with NAFLD, and it aggravates NAFLD to more severe forms of NASH, hepatocirrhosis, and HCC, leading to a metabolically worse phenotype.

Figure 2

NAFLD development is caused by an imbalance in the intrahepatocellular fatty acid (FA) metabolism. Hepatic TG accumulation is promoted when the FA input is greater than the FA output in the liver. The greater part of FA taken up by liver is mainly derived from the lipolysis of subcutaneous adipose tissue TG. Another major source of FA in the liver is derived from de novo lipogenesis that converts excess glucose into FAs. On the other hand, the consumption of FA is possible through the signaling pathway involved in lipolysis, β-oxidation, and TG secretion (→: signaling pathways related with TG accumulation by FA, →: signaling pathways related with the consumption of FA).

Figure 3

Multiple-hits pathogenesis of NAFLD and NASH. NAFLD begins with hepatic lipid accumulation and insulin resistance, and progresses to NASH with the concert of various factors such as inflammation, endotoxin, organokines (adipokines and hepatokines), and oxidative stress. (▪: Factors related with multiple-hits).

Figure 4

Current therapeutic targets for pharmacological treatment of NAFLD and NASH. There are no FDA-approved medications for patients with NAFLD/NASH so far. Currently, various pharmacological therapeutic candidates are being applied to the clinical trials. The illustration demonstrates the targeted pathway and phenotype for treatment of patients with NAFLD and NASH.

Figure 5

Adipokines as diagnostic markers and therapeutic targets in NAFLD and NASH. Adipokines that are secreted from adipose tissues are classified into anti-inflammatory adipokines and pro-inflammatory adipokines. Anti-inflammatory adipokines including adiponectin, irisin, and ghrelin inhibit the development and progression of NAFLD and NASH, whereas pro-inflammatory adipokines including leptin, resistin, and visfatin promote the development and progression of NAFLD and NASH.

Figure 6

Hepatokines that are secreted from the liver are closely associated with the progression from NAFLD to NASH to HCC. Hepatokines including Fetuin-A, Fetuin-B, RBP4, and FGF19 play an important role in NAFLD and NASH. They are associated with hepatic lipid accumulation, insulin resistance, and inflammatory signaling pathways. Additionally, ANGPTL4 and 8 tend to function in opposite ways in HCC tumorigenesis.