Chronic excessive alcohol drinking can lead to serious liver injury. Alcoholic liver disease or
alcohol-associated/related liver disease (ALD) is characterized by steatosis, inflammation, and
fibrosis, which can lead to cirrhosis, cancer and multiple complications. While significant progress has
been made, much has yet to be learnt about the pathogenesis of alcohol-induced liver injury to
develop effective therapy and diagnosis. Extracellular vesicles (EVs) are intracellular vesicles
released by cells into the extracellular space in response to various physiological and pathological
signals. Increased production of EVs in ALD has been found to contribute to the pathogenesis of ALD
in a significant way. But the mechanism of enhanced EV production under chronic alcohol exposure
is not known.
On the other hand, autophagy is an evolutionarily conserved process, and its disturbance can
contribute to ALD with the molecular pathway undefined. Interestingly, we find that EVs produced in
autophagy deficient mice carry the same molecular signatures as those generated by alcohol-fed
mice. Our preliminary findings support a hypothesis that EV production in ALD condition could be
driven by a unique regulatory pathway involving autophagy inhibition, activation of NRF2 and
upregulation of SDCBP2 and that these molecules can have functional impact on the liver pathologies
via the EVs. To examine this hypothesis, we have proposed two specific aims. In Aim 1, we will
determine the mechanism of EV production in a mouse model of ALD. Here we will examine how
autophagy deficiency following chronic alcohol exposure could promote EVs production. We will
examine the molecular link from NRF2 to SDCBP2, both of which are elevated in expression in
genetically modified autophagy deficient livers and in chronic alcohol-fed livers. Unlike the steady
generation of EVs in basal conditions, this is a regulated pathway to enhance EV production in
response to the pathological stimulation of alcohol uptake. In Aim 2, we will determine the
contribution of SDCBP2 via enhanced EV production to alcoholic liver pathogenesis. We will examine
the effect on inflammation via M1 polarization and other liver pathology.
These studies will elucidate an important mechanism that regulate EV production in ALD (a short-
term goal), which will significantly advance the field as the identification of new molecular targets
could potentially stimulate therapeutic and diagnostic development in future R01-based studies (an
intermediate term goal), leading to improved management of ALD (a long-term goal).
