Human fatty liver disease: old questions and new insights

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.

Fig. 1

The disease spectrum of nonalcoholic fatty liver disease. (A) Schematic of progression of NAFLD. The accumulation of TG within lipid droplets in hepatocytes causes steatosis. Steatosis associated with inflammation, cell death, and fibrosis is referred to as NASH, which can progress to cirrhosis. Individuals with cirrhosis have an increased risk of hepatocellular carcinoma. (B) Histological sections illustrating normal liver, steatosis, NASH, and cirrhosis. Collagen fibers are stained blue with Masson’s trichrome stain. The portal triad (PT), which consists of the hepatic artery, portal vein, and bile duct, and the central vein (CV) are shown.

Fig. 2

Metabolism of TG in the liver. The three major sources of FFAs are diet, endogenous synthesis, and peripheral tissues. FFAs have four possible fates. They can be metabolized by β oxidation (β-OX) in mitochondria, esterified and stored as TG in lipid droplets, used to form other lipids (not shown), or packaged with apoB into VLDL and secreted into blood. Processes that increase FFA and TG input or reduce FFA and TG output cause hepatic steatosis. Carbohydrate intake increases glucose and insulin levels, which activate two transcription factors in the liver that promote de novo lipogenesis: ChREBP and SREBP-1c. Insulin inhibits lipolysis in adipose tissue by suppressing ATGL. Chylo, chylomicron; TCA, tricarboxylic acid.