Mechanisms of Nonalcoholic Steatohepatitis
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with metabolic syndrome, whose incidence is rising at a fast pace in the world. Modern lifestyle and high-fat diet are considered to be the major factors for the development of NAFLD. At least one-third of the US population is believed to have NAFLD, and it is estimated that about 6 million individuals in the US general population have progressed to nonalcoholic steatohepatitis (NASH), and about 600,000 to NAFLD-related cirrhosis. A significant number of these patients are American War Veterans. Lifestyle, diet, and obesity are major factors that cause NAFLD. Although a majority of individuals with NAFLD demonstrate just fat accumulation in the liver without significant inflammation or fibrosis, NAFLD progresses to very aggressive NASH in up to 30% of the patients. However, it is not known "why only a subpopulation is predisposed to develop progressive and severe form of NASH." This disease in several instances goes undetected, and invasive and painful biopsy may not always confirm pathological development. The frustrating fact is that there are no reliable serum (blood) markers indicative of progressive NAFLD. Thus, NAFLD can progress silently to the end-stage liver disease with liver transplantation as the only life-saving option. Unfortunately, current animal models do not mimic the entire spectrum of the pathology of human NAFLD, especially fibrosis and cirrhosis. It is thus clear that factors other than diet or lifestyle predispose the human subpopulation to develop NASH. Our work indicates, for the first time, that abnormality in a protein known as augmenter of liver regeneration (ALR) or ALR deficiency can be a critical factor in the development of hepatic steatosis and NASH. We have developed a mouse model in which we deplete ALR specifically from the liver shortly after birth. This liver-specific ALR knockout (ALR-L-KO) mouse rapidly develops profound fat accumulation in the liver between 1 and 2 weeks in association with severe mitochondrial dysfunction and degeneration and strongly reduced levels of the energy component (ATP). This pathology is accompanied by excessive death of the liver cells, which then regenerate (presumably from different pool of cells). Subsequently, the liver develops inflammation and exhibits continued cell death and regeneration accompanied by development of fibrosis and eventually liver cancer by 1 year. ALR levels are also lower than normal in alcohol-induced fatty liver and in mice that genetically develop fatty liver disease. More importantly, humans with advanced NASH also have low liver and blood ALR levels. Interestingly, we observed several alterations in the ALR gene that produce the active component (the ALR protein), some of which occur at greater frequency. We postulate that these alterations may be related to NASH development. ALR-L-KO mice appear normal and tend to their daily functions as well as the control mice despite the underling pathological development. Thus, it mimics human NASH, the early or intermediate pathology of which may remain clinically undetected without invasive and painful diagnostic technique. All of the characteristics of the ALR-L-KO mouse described above represent the concept of NASH development in human. Since NASH is a mitochondrial disorder and ALR is a mitochondrial protein with critical functions, our overarching hypothesis is that abnormality in ALR protein or ALR deficiency renders the human subpopulation susceptible to develop NASH and cirrhosis. We contend that the ALR-LKO mouse is an ideal model to understand mechanisms of human NAFLD/NASH. Our specific aims are: Aim 1: To determine the mechanisms of mitochondrial abnormalities in ALR-L-KO mice. Aim 2: To dissect the mechanisms of progressive NAFLD/NASH in ALR-L-KO mice. In both aims, we will use liver and blood from ALR-L-KO mice and also deplete ALR from control liver c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510370
Entities
People
- Chandrashekhar R Gandhi
Organizations
- United States Army