Mitochondrial involvement in the metabolic defects evoked by hepatocyte-specific BBSome deficiency

Abstract

Listen

Translate article

The BBSome, a protein complex of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as an important regulator of metabolic function. BBSome deficient human and mice display several metabolic features including obesity and type 2 diabetes. Here, we show that mice lacking the BBSome specifically in liver which were generated by crossing the Bbs1fl/fl mice with liver-specific (albumin) AlbCre mice exhibit significantly higher lipid droplets in liver, by Oil Red-O staining, and in primary cultured hepatocytes (5.7%±0.4% vs 2.4%±0.6%, control), and by Transmission electron microscope (TEM). AlbCre/Bbs1flox also have elevated fasting glucose (169± 14 vs 136±8 mg/dL, p<0.05) and impaired insulin sensitivity. In addition, insulin-induced activation of AKT was significantly decreased in the liver (2.6±0.07 vs 6.6± 0.34 AU, p<0.05), but not in white adipose tissue and skeletal muscle, of AlbCre/Bbs1flox mice. Using immunohistochemistry, we found that insulin receptor level in plasma membrane was decreased by 24.2±6.8% in primary cultured hepatocytes derived from AlbCre/Bbs1flox mice which explains the insulin resistance. Our previous work implicating the BBSome in the regulation of mitochondria led us to hypothesize that mitochondria dysfunction contributes to the development of metabolic defects in AlbCre/Bbs1flox mice. TEM studies revealed that mitochondria were significantly larger and longer in hepatocytes of AlbCre/Bbs1flox mice than controls. This was associated with decreased levels of Dynamin-related protein 1 (DRP1), which critically regulates mitochondrial function through fission. Next, we asked whether the mitochondrial defects may explain the insulin receptor mistraffcking in BBSome deficient hepatocytes. To test this, hepatocytes were infected with feline immunodeficiency virus that express an active mutant form of DRP1 (FIV-DRP1S637A). Interestingly, insulin receptor localization in the plasma membrane was significantly higher in hepatocytes of Bbs1fl/fl/AlbCre­ mice infected with FIV-DRP1S637A pointing to mitochondrial defects as the underlying cause of insulin receptor mislocalization induced by hepatic BBSome deficiency. Taken together, these findings demonstrate that BBSome regulation of metabolic function involve mitochondria. NIH and VA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.