세미나

Abstract
Mechanisms underlying pathogenesis of
metabolic dysfunction-associated steatotic liver disease (MASLD)
KyeongJin Kim
Departments of Biomedical Sciences, College of Medicine; Program in Biomedical Science
& Engineering; Research Center for Controlling Intercellular Communication (RCIC),
Inha University, Incheon 22212, Korea
Obesity predisposes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver
disease (MASLD), but underlying mechanisms are incompletely understood. Previously, we identified
that potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in
livers from obese mice and patients with MASLD/MASH (metabolic dysfunction-associated
steatohepatitis), where it acts to degrade pleckstrin homology domain leucin-rich repeat protein
phosphatase 2 (PHLPP2) to prolong insulin signaling by dephosphorylating Akt. Here we further
investigated putative upstream regulators and downstream effectors of increased Kctd17 in obesityassociated T2D and MASLD.

Hepatocyte Kctd17 expression is increased in high-fat diet (HFD)-fed
mice by increased sterol regulatory element-binding protein 1c (Srepb1c) activity. Forced hepatocyte
Kctd17 expression induces glucose intolerance and hepatic lipid accumulation even in normal chow
diet (NCD)-fed mice. Conversely, hepatocyte-specific Kctd17 deletion or treatment with Kctd17-
directed antisense oligonucleotide (ASO) in HFD-fed mice improves glucose intolerance and fatty
liver, by decreasing carbohydrate response element-binding protein (Chrebp) protein stability. These
results suggest a novel means of regulation of Chrebp, by Srebp1c-mediated increase in Kctd17. We
anticipate that interrupting this feed-forward lipogenic loop by targeting Kctd17 may prove effective
for the twin glucose and lipid abnormalities that occur in the obese liver. Recently, we further
investigated the role of Kctd17 in the progression of MASH-induced fibrosis or HCC (hepatocellular
carcinoma). We will briefly discuss how hepatocyte Kctd17 contributes to subsequent development
of MASH/HCC, and the findings suggest translational potential of Kctd17 inhibitors in patients with
steatotic liver disease (SLD).