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Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by increased lipid accumulation in the liver. Though the exact cause of manifestation is largely unknown, insulin resistance, type 2 diabetes and obesity are strongly associated with development and progression of MASLD. Recent literature emphasizes the role of genetics in the pathogenesis of MASLD. In several genome wide association studies, polymorphisms in Tribbles 1 (TRIB1) are significantly associated with MASLD. However, molecular mechanisms underlying TRIB1 and increased hepatic lipid accumulation are poorly understood. In this study we hypothesized that TRIB1 controls hepatic lipid homeostasis by regulating C/EBPα expression which is a known regulator of de novo lipogenesis (DNL). To understand the mechanism of action, we generated TRIB1, CEBPA, and RFWD2 gene knockouts in HepG2 cell line and in primary human hepatocytes and overexpression of TRIB1 in HepG2s. Knockout and overexpression cell lines were challenged for 24-72h with a cocktail of glucose, fructose, and insulin to mimic DNL conditions and evaluated lipid accumulation via confocal microscopy and gene expression analysis to understand mechanism of action. Lack of TRIB1 in primary human hepatocytes significantly increased lipid content compared to control cells under DNL conditions. Knockout of CEBPA and RFWD2 in HepG2’s significantly reduced lipid accumulation compared to controls. Overexpression of TRIB1 led to reductions in CEBPA gene expression and DNL; however, as TRIB1 overexpression waned, so did these attenuations. These data suggest that, while TRIB1 may regulate CEBPA expression, high expression levels are required to lessen the disease phenotype in this cell system. Strong TRIB1 inducers, or alternative regulators of CEBPA, may be required to leverage this mechanism in future therapeutics. Disclosure T. Dehghani: Employee; insitro. L. Shewade: Employee; insitro. K. Guo: Employee; insitro. D. Lloyd: Employee; insitro. S. Satapati: None.
Dehghani et al. (Fri,) studied this question.