Obesity predisposes to type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), but underlying mechanisms are incompletely understood. Potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in the livers from obese mice and humans. This study investigated the mechanism of increased Kctd17 and whether it is causal to obesity-induced metabolic complications. In obese, Hepatocyte Kctd17 expression was increased in high-fat diet (HFD)-fed mice due to increased Srebp1c activity. HFD-fed hepatocyte-specific Kctd17 knockout (L-Kctd17) or Kctd17 antisense oligonucleotide (ASO)-treated mice show improved glucose tolerance and hepatic steatosis. Kctd17 induced O-GlcNAcase (Oga) protein degradation, resulting in increasing carbohydrate response element-binding protein (Chrebp) protein, so concomitant Oga knockout negated the metabolic benefits of hepatocyte Kctd17 deletion. Srebp1c-induced hepatocyte Kctd17 expression in obesity disrupted glucose and lipid metabolism by stabilizing Chrebp. In NASH, NASHprovoking diet-fed L-Kctd17 or Kctd17 ASO-treated mice showed reduced hepatic stellate cell (HSC) activity and liver fibrosis. Kctd17 induced zinc finger and BTB domain containing 7b (Zbtb7b) protein degradation, which reduced the transcription level of serine protease inhibitor a3k (Serpina3k). Decreased Serpina3k induced hepatic stellate cell activation and increased liver fibrosis through the proteaseactivated receptor 2 (Par2)-mediated transforming growth factor beta (TGFβ) pathway. Conversely, forced hepatocyte Serpina3k mitigated NASH-provoking liver fibrosis by reducing activation of hepatic stellate cells. In summary, those results suggest that hepatocyte Kctd17 is a crucial factor that regulates obesityinduced fatty liver and liver fibrosis. Consequently, Kctd17 would proffer a new therapeutic target for the treatment of obesity-induced T2D, NAFLD, and NASH.