ABSTRACT
Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, ß-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r2 = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of ß-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via ß-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.
Subject(s)
PPAR gamma , beta Catenin , PPAR gamma/metabolism , PPAR gamma/genetics , Humans , Animals , beta Catenin/metabolism , beta Catenin/genetics , Mice , Male , Fatty Liver/metabolism , Fatty Liver/pathology , Fatty Liver/genetics , Female , Hepatocytes/metabolism , Hepatocytes/pathology , Cell Line , Mice, Inbred C57BL , Disease Models, Animal , Liver/metabolism , Liver/pathology , Middle Aged , Adult , Fatty Acid-Binding Proteins/metabolism , Fatty Acid-Binding Proteins/genetics , CD36 Antigens/metabolism , CD36 Antigens/geneticsABSTRACT
Non-secretory multiple myeloma (NSMM) is a rare type of multiple myeloma characterized by the absence of the M protein, making its diagnosis challenging. Here, we report a 67-year-old female patient eventually diagnosed as NSMM with positron emission tomography-computed tomography (PET/CT) imaging as a clue.