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Zebrafish Models of Human Disease Non-Alcoholic Fatty Liver Disease
Disease is the result of a breakdown or Fatty liver disease, or overaccumulation of fat in
perturbation of the systemic homeostasis in an the liver leading to inflammation and fibrosis, is
animal. This perturbation may be the result of usually associated with alcoholism or obesity.
genetic mutations or variations or Globally, non-alcoholic fatty liver disease
environmental pressures. Understanding the (NAFLD) is found in those with high BMI and
disease requires us to look deeply into the body fat. It is thought that high adipose tissue
organism, the tissues, the cells and sometimes fat deposits lead to the import of fat for storage
the molecules. Working with humans, one into the liver. Higher levels of fat in the liver
cannot look deep enough or tinker far enough causes inflammation triggering steatohepatitis.
to see cause and effect relationships. Animal The lipid accumulation damages hepatocytes
models offer a new window or a new tool to and fibrosis sets in leading to cirrhosis.
strengthen our hands and deepen our However, this pattern is not always observed in
understanding. We use zebrafish (Danio rerio), Indians and Southeast Asians. In this population
a natural resident of the rivers and paddy fields there is a higher-than-western-populations
of India, as a surrogate for humans in our quest prevalence of NAFLD in lean non-alcoholic
to understand disease pathophysiology. This individuals. Thus, Indians appear to be prone to
small vertebrate breeds well in captivity and a type of fatty liver disease independent of
their transparent embryos have offered us these two factors. In our studies in a zebrafish
many new insights into vertebrate embryonic model of fatty liver, we have been able to
development. These chemically permeable identify inflammation as an independent cause
embryos have also been instrumental in of fatty liver. Through our studies with systemic
discovering new drugs and chemical modulators overexpression of the inflammatory cytokine
of biological pathways. Over the years, we have Interleukin 6 (IL6), we find that liver metabolism
used genome editing, antisense oligo gets reset to shunt glucose metabolism into the
technologies and transgenics to perturb gene fat synthesis pathway. The liver accumulates
expression to create models of human rare large amounts of fat that can compromise
genetic disorders, birth defects and lifestyle hepatocyte function. We also observe
disorders in the zebrafish. Our studies have indications of mitochondrial dysfunction. We
revealed novel phenotypes, uncovered new are attempting to decipher the molecular effect
molecular pathways, mediators, and regulators of systemic IL6 overexpression and IL6 receptor
of these diseases. We have also used chemical signaling in the hepatocytes. Using zebrafish
screens to identify novel small molecule chemical screens, we are also attempting to
modulators that can alleviate the phenotypic identify small molecules that can reverse this
manifestations of the disease in the model. metabolic shift and lipid imbalance in
hepatocytes.
Publications
Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver.
Singh MK, Jayarajan R, Varshney S, Upadrasta S, Singh A, Yadav R, Scaria V, Sengupta S, Shanmugam D, Shalimar,
Sivasubbu S, Gandotra S, Sachidanandan C. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 May;1866(5):158905.
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