Investigating the sex-specific roles of PKLR and CHCHD6 in insulin resistance and NAFLD - PROJECT SUMMARY/ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is increasingly being recognized as the hepatic manifestation of
metabolic syndrome that can lead to cardiovascular diseases. Currently, very little is known about the genetic
and molecular factors underlying NAFLD. Besides, no known therapeutic strategies are available to prevent or
treat the condition. To address this problem, we applied an integrative multi-omics approach using an extensively
phenotyped mouse cohort, Hybrid Mouse Diversity Panel (HMDP) and identified many known and several novel
candidate genes regulating NAFLD. We further validated two novel candidates, pyruvate kinase, liver isoform
(PKLR) and coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6). When these two genes were
knockdown in male mouse models of steatosis, both NAFLD and insulin sensitivity improved as measured by
intrahepatic triglyceride accumulation levels, glucose- and insulin- tolerance tests, and fasting glucose and
insulin levels. Follow-up bioenergetic analyses revealed these two genes regulated mitochondrial metabolism in
developing steatosis and insulin resistance. When we further expanded this to include the female HMDP strains,
we found that these two genes have no effect. Specifically, correlation analyses revealed PKLR and CHCHD6
do not develop NAFLD and insulin resistance in female strains, respectively. To further our understanding on
the gene-by-sex interactions mediated by these two genes in regulating mitochondrial metabolism and in
developing NAFLD and insulin resistance, I have proposed three interrelated aims to examine 1) mechanisms
underlying PKLR- and CHCHD6- mediated lipid metabolism, 2) metabolic consequences of liver-specific
overexpression or knockdown in female mouse models of steatosis, 3) gene networks and cellular heterogeneity
altered by liver-specific overexpression or knockdown in mouse models of advanced NASH and fibrosis.
Furthermore, I have developed a detailed five-year career development plan that includes two-year
mentored phase (K99 phase) followed by three-year independent phase (R00 phase) for my transition into an
independent academic career. I have included a highly talented and distinguished panel of advisors including
Drs. Aldons J. Lusis, Orian Shirihai, Neil Kaplowitz, Andrea Hevener, Peter Tontonoz, and Steven Bensinger, to
assist in my transition to independence. I have significant experience in studying how host genetics and sex
differences dictate the outcomes of complex disease traits using systems genetics analyses. I now plan to
expand my training in liver and mitochondrial physiology, lipid metabolism, metabolic phenotyping and single cell
sequencing. Overall, the goal is to advance my training to become an independent investigator and perform
research bridging systems genetics, mitochondria and liver metabolism.
