Vineeth Daniel Poovannalil, PhD

American Liver Foundation Postdoctoral Research Fellowship Award
$25,000 over one year

Mayo Clinic, Rochester

Lipotoxic ER stress upregulates S100A11 in an epigenetic manner contributing to liver inflammation in MASH
Mentor: Harmeet Malhi, MBBS

Metabolic dysfunction associated steatohepatitis (MASH) formerly known as Non-alcoholic steatohepatitis (NASH) is a globally concerning chronic liver disease. Statistics report 1.5-6.5% US adults to have MASH. Clinical conditions like obesity, type 2 diabetes mellitus (T2DM), dyslipidemia is strongly linked with MASH. MASH results from abnormal routing of excess circulating fat to the liver, followed by associated inflammation and fibrosis. This ectopic fat buildup in the hepatocytes (most abundant liver cells) triggers “Hepatic Lipotoxicity". Palmitate (PA), a saturated fatty acid, is notably abundant in the liver and plasma of MASH patients. Recent studies indicate that PA induces endoplasmic reticulum (ER) stress in hepatocytes and prompts the release of cellular stress-dependent inflammatory signals. These signals are secreted outside the cells through nanosized vesicles called extracellular vesicles (EVs). Damage associated molecular pattern (DAMP) proteins are notable inflammatory markers extruded in stressed cell secretomes. Additionally, lipotoxicity can also impact epigenetic mechanisms and dysregulate gene expression. Epigenetic pathways are environmental stress-dependent mechanisms that modify the accessibility of DNA sequence, influencing the way genes are read into proteins inside a cell. Epigenetic pathways modify the typical cellular phenotype without changing the underlying DNA sequence. Thus, our aim is to find epigenetically controlled inflammatory extracellular vesicle cargos linked to lipotoxic ER stress, potentially contributing to MASH-related liver inflammation. From our initial studies, we observed S100A11, a bona fide DAMP protein as a significant EV cargo in PA stimulated conditions. S100A11 has an emerging association with MASH. Thus, through our research proposal we aim to demonstrate how PA induced lipotoxic ER stress upregulates S100A11 expression. We also aim to delineate epigenetic pathways within the PA induced regulation of S100A11 which may be amenable to pharmacological interventions.