Autophagy is a finely regulated catabolic pathway that is inhibited by nutrient-rich condition, further physiologically inhibited in metabolic syndrome such as obesity and metabolic-associated fatty liver disease (MAFLD). A master regulator of autophagy is mechanistic target of rapamycin (mTOR), which acts as a nutrient sensor and is regulated by hormones, growth factors, cell-stress signals. mTOR inhibits autophagy by phosphorylating Unc-51-like kinase-1 (ULK1), which is the important kinase in autophagy. However, autophagy can also be downregulated by mTOR-independent mechanisms. Another, less well understood, nutrient sensor is PAS domain-containing serine/threonine kinase (PASK). We show here that PASK blocks autophagy in nutrient-rich conditions by promoting mTOR-independent proteasomal degradation of ULK1. Proteomics and immunoprecipitation approaches showed that PASK complexes with ULK1 and the E3-ubiquitin ligase tripartite-motif-25 (TRIM25), which promotes ULK1 ubiquitination and degradation. PASK-dependent downregulation of autophagy also contributes to MAFLD. High-fat diet-fed mice that developed MAFLD demonstrated upregulated PASK expression, low ULK1 protein levels, and suppressed autophagy in their liver, and these changes were not observed in Pask-knockout mice. Thus, PASK negatively regulates autophagy by facilitating ULK1 degradation. This provides insights into the pathological mechanisms underlying metabolic-syndrome conditions and suggests that PASK could be a novel therapeutic target for these conditions.