Altered Cellular Response to Lipids in Aging

Introduction
 » Goal
 » Specific Aims  

Subprojects

» Autophagy and lipid metabolism

» Lipid accumulation and autophagy 

» Aging and the metabolic syndrome

» FFA and immune cells

Members
Mark Czaja 

Rajat Singh

Pallavi Singh

Kiran Baikati

Yongjun Wang

Studies in Project 4 will examine the effect of decreased autophagy on cellular responses to free fatty acids ( FFA ) in aging.

    A major burden of disease in the aged is due to the metabolic syndrome which is characterized by obesity, dyslipidemia and insulin resistance. Insulin resistance leads to increased levels of circulating FFA that can cause cellular lipid accumulation or altered function in any organ in the body. Dr. Czaja's laboratory has long been involved in studies of the molecular mechanisms by which lipid accumulates in the hepatic manifestation of the metabolic syndrome termed nonalcoholic fatty liver disease and leads to liver injury (steatohepatitis).

  Recent investigations in Dr. Czaja's laboratory have demonstrated a critical role for autophagy in the regulation of hepatocellular lipid stores, suggesting that the decrease in autophagy that occurs with aging may be a mechanism for fat accumulation in this organ. Other studies in T cells and dendritic cells have shown that increased FFA levels affect the activation of these cells. This finding indicates that the exposure of immune cells to excessive FFA levels may contribute to the impairment in immune function that accompanies aging. Together these studies and others have led to the central hypothesis of this project that the decrease in autophagy that occurs with aging alters cellular responses to FFA, leading to the development of hepatic steatosis and immune system dysfunction.

The investigations in this project will employ in vitro and in vivo models of impaired hepatocyte and immune cell autophagy in order to:

1)      establish that autophagy regulates hepatocyte lipid accumulation by mediating the breakdown of triglyceride stored in lipid droplets;

2)      demonstrate that lipid accumulation down regulates autophagy and sensitizes the hepatocyte to oxidant injury;

3)      determine that the aging-induced decline in autophagy promotes the development of hepatic steatosis, injury and insulin resistance; and

4)   establish that a depression of T cell and dendritic dell activation by FFA decreases immune function with aging.

Histology of steatohepatitis

Increased lipid droplets with an inhibition of macroautophagy

Autophagosomes (arrows) associated with a lipid droplet in mouse liver