Autophagy

Nonalcoholic fatty liver disease (NAFLD) is a lifestyle-related disease caused by excessive nutrient intake, and the number of NAFLD patients has been increasing in recent years. Effective treatment has yet to be developed, and in some cases, the disease progresses to serious conditions such as cirrhosis and liver cancer. Therefore, there is a need to elucidate the pathogenesis of NAFLD. Recently, we demonstrated that upregulation of Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein), in association with excessive fat intake, impaired autophagy and played a pathogenic role in NAFLD. Below is an overview of the first report showing that autophagy is altered by excessive fat intake, which is an environmental factor, and thereby contributes to NAFLD pathogenesis.

p62/Sqstm1: The molecule that links autophagy to the Keap1-Nrf2 system

The lysosome is a cellular organelle whose main function is degradation. It is primarily known as the place where extracellular materials and plasma membrane proteins internalized by endocytosis are degraded. But, it can certainly degrade intracellular components as well (Figure 1). Autophagy is a “cellular function in which the cell degrades its own components in the lysosome.” Although often mistaken for a type of cell death, autophagy is a degradative process that mostly protects the cell from cell death.

Autophagy is broadly classified into “macroautophagy,” “microautophagy,” and “chaperone-mediated autophagy” (Figure 1). Among them, macroautophagy has the largest degradative capacity and has been extensively studied in many species from yeast to animals and plants. In contrast, microautophagy and chaperone-mediated autophagy have been studied primarily in yeast and mammals, respectively, and their occurrence and molecular mechanisms are not fully understood (microautophagy might be the same process as the formation of multivesicular bodies in mammals). For this reason, macroautophagy is commonly referred to by the term autophagy, which will be used hereafter in this article.

Many of the molecules involved in autophagy were identified in genetic studies of the budding yeast in early 1990s by Dr. Yoshinori Ohsumi (currently of the Tokyo Institute of Technology) and his colleagues [1]. The ATG1 through ATG41 genes have been known as of August 2016. Most of these genes are required for selective autophagy, which targets specific substrates for degradation. For example, ATG30 is required only for autophagy of peroxisomes (pexophagy), and ATG32 is required only for autophagy of mitochondria (mitophagy). In contrast, the 15 genes known as the “core ATG genes” (ATG1 – 10, 12 – 14, 16, 18) are required for all types of autophagy, including the non-selective “ordinary autophagy” that is induced during starvation. These genes are highly conserved in other organisms including mammals. The detailed functions of these genes have been reviewed elsewhere [2, 3].