Determining hepatocyte-specific mechanisms by which Ube4A regulates NAFLD/NASH

Project summary
Obesity is a major risk factor for NAFLD/NASH. In obesity, energy accumulation causes metabolic dysfunction
and endoplasmic reticulum (ER) and oxidative stress, leading to tissue inflammation and injury, which are
hallmarks of NASH. The DNA damage response and unfolded protein response are vital to maintain the integrity
of cellular genome and proteome. The ER maintains proteostasis via ER-associated protein degradation and
unfolded protein response. Metabolic dysfunction alters ER-associated protein degradation and unfolded protein
response, leading to ER stress, caspase activation and cell death. Moreover, increased oxidative stress
enhances DNA damage-induced cell death. Defining how these pathways integrate to dictate cell metabolism
and survival is the long-term goal of The Chakraborty lab. The objective of this proposal is to decipher the role
of the E3 ubiquitin ligase Ube4A in the obesogenic IP6K1 protein-mediated hepatocyte metabolic dysfunction
and DNA damage response and unfolded protein response mediated hepatocyte survival and NAFLD/NASH.
The overarching hypothesis is that Ube4A maintains metabolic homeostasis and protects hepatocytes from
stress-induced death, delaying the development and progression of obesity and NAFLD/NASH. The rationale is
that determining the role of Ube4A in NAFLD/NASH and the mechanisms by which it regulates hepatocyte
metabolism and survival will provide new therapeutic opportunities. Our specific Aims will test the following
hypotheses: (Aim 1) Test the impact of whole-body- and hepatocyte-Ube4A deletion on metabolic dysfunction,
liver injury, and NAFLD/NASH in mice; (Aim 2) Determine mechanisms of Ube4A-mediated IP6K1 inhibition and
its impact on metabolic dysfunction and NAFLD/NASH in mice; (Aim 3) Decipher the mechanisms by which
Ube4A regulates hepatocyte survival. The contribution is significant and transformative because it is expected
to unravel the role of a novel pathway that regulates obesity, insulin resistance and hepatic steatosis and
distinguish the hepatocyte-specific impact of this pathway on NAFLD/NASH. Moreover, it is the first step to
defining the mechanisms of how Ube4A regulates hepatocyte metabolism and survival and how the obesogenic
protein IP6K1 is modulated in vivo. These exciting findings could lead to development of new therapeutic
approaches to treat obesity and NAFLD/NASH. The proposed research is innovative as it will utilize exciting new
tools to unravel a novel pathway that regulates cell metabolism and survival, which is therapeutically relevant
and has broad implications for many diseases.

Grant Number: 7R01DK132162-04
NIH Institute/Center: NIH
Principal Investigator: Anutosh Chakraborty