Lipid droplets (LDs) are endoplasmic reticulum (ER)-derived repositories of neutral lipids that function as cellular hubs of lipid metabolism. Imbalances in lipid utilization and secretion can lead to the aberrant deposition of triacylglycerol in hepatocyte LDs (i.e., hepatic steatosis). Metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH) can progress to liver cirrhosis and hepatocellular carcinoma and are a growing public health crisis. However, our understanding of the mechanisms that govern the channeling of ER neutral lipids in hepatocytes towards cytosolic LDs or secreted lipoproteins remains incomplete. To systematically uncover mechanisms of hepatic neutral lipid flux, we performed a series of CRISPR-Cas9 screens under different metabolic states, providing an extensive compendium of lipid storage genetic modifiers. Analysis of chemical-genetic interactions identified CLIC-like chloride channel 1 (CLCC1) as a regulator of neutral lipid storage, and genetic variants in CLCC1 are associated with altered serum lipids in humans. Loss of CLCC1 resulted in the buildup of large LDs in cultured hepatoma cells and liver-specific knockout of CLCC1 in mice caused profound liver steatosis. Remarkably, LDs accumulated in the lumen of the ER, were apolipoprotein B positive, and were microsomal triglyceride transfer protein dependent, indicating that these lumenal LDs are aberrant lipoproteins. Finally, structure homology searches identify a domain in CLCC1 that is homologous to yeast Brl1p and Brr6p, factors that promote the fusion of the inner and outer nuclear envelopes during nuclear pore complex assembly in yeast. Indeed, loss of CLCC1 resulted in the accumulation of nuclear membrane herniations consistent with impaired nuclear pore complex assembly. Our data identify CLCC1 as the human Brl1p/Brr6p ortholog and support a model in which CLCC1-mediated membrane remodeling promotes nuclear pore complex assembly and hepatic neutral lipid flux.