Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form MASH (metabolic dysfunction-associated steatohepatitis) are major global health challenges with increasing prevalence. MASH is characterised by lipid accumulation and inflammation, and is associated with the development of life-threatening diseases, including fibrosis, cirrhosis and liver cancer. Whilst lipid metabolism is a central feature of MASLD and leads to disease progression, many attempts to target defective lipid metabolism in MASLD have been unsuccessful.
To uncover novel regulators of lipid metabolism in MASLD, our lab conducted five independent genome-wide CRISPR-Cas9 knockout screens in Hep2 liver cells. Through these screens, we identified amyloid beta precursor protein binding family B member 2 (APBB2) as a novel regulator of hepatic lipid accumulation. While APBB2 has previously been associated with Alzheimer’s disease, its function in lipid metabolism and MASLD remains largely unclear.
Using sgRNA knockout in HepG2 cells coupled with 14C tracer experiments, we show that deletion of APBB2 promotes lipid accumulation through suppression of mitochondrial fatty acid oxidation. Mechanistically, deletion of APBB2 reduces expression of carnitine palmitoyl transferases I and II (CPT1 and CPT2), thereby limiting fatty acid entry into mitochondria for oxidation, which is further associated with a substrate switch towards increased glucose utilization and de novo lipogenesis (from glucose), further driving ectopic lipid accumulation.
Together, this study identifies APBB2 as a novel regulator of hepatic lipid metabolism, and further investigation into the role of APBB2 in oxidative fatty acid metabolism may help us define APBB2 as a new therapeutic target for MASLD.