Current Research Projects

Project #1: Non-alcoholic fatty liver disease (NAFLD)

One of the major complications of metabolic syndrome affecting the liver, in the absence of excessive alcohol, is non-alcoholic fatty liver disease (NAFLD). It is estimated that 20-30% of the population worldwide are affected by NAFLD. Recent studies have also revealed that NAFLD is more prevalent in men than women, with men exhibiting severe NAFLD symptoms. Besides, NAFLD has a tremendous burden on our global healthcare systems with yearly expenditures of well over a hundred billion dollars. Added to that, there are no prevention and/or treatment options for NAFLD other than reducing the risk factors such as weight reduction. To this end, we used an integrative multi-omics approach (Figure 1) using an extensively phenotyped mouse cohort, the Hybrid Mouse Diversity Panel (HMDP) and identified several novel candidates and validated few of them (PKLR and CHCHD6). The next steps include characterizing them further to understand their mechanistic functions. 

Figure 1: Overview of multi-omics approach and its application to identify and validate PKLR & CHCHD6. Adapted from Chella Krishnan et al. (2018) Cell Systems 6(1):103-115.e7.

Project #2: Obesity

Among the sexually dimorphic autosomal genes in adipose in our HMDP, lipocalin-2 (LCN2) stood out as one of the most strongly and significantly downregulated genes in female adipose (~ 7-fold F < M, P = 1.9E-30). LCN2 is a secreted protein involved in innate immunity and has also been associated with several cardio-metabolic disease states. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males. To this end, we used a systems genetics approach and studied the genetics of LCN2 expression and associated clinical traits in both sexes of HMDP. The correlation analyses revealed striking female-specific associations in obesity, insulin resistance, steatosis and dyslipidemia (Figure 2). The next steps include characterizing them further to understand their mechanistic functions.

Figure 2: Sex-specific associations of adipose LCN2 with metabolic traits in the HMDP population. Adapted from Chella Krishnan et al. (2019) Molecular Metabolism 30:30-47.