Complications (Co-Leaders: Joseph Witztum, Rohit Loomba and Jake Lusis)

Despite advances in the treatment of hyperglycemia, hypertension and hyperlipidemia, the macrovascular and microvascular complications of diabetes are still devastating. Moreover, there is now an epidemic of liver disease associated with obesity and diabetes, that includes hepatic steatosis, NAFLD and liver cancer. Highlights include the following.


  1. Systems biology analysis reveals role of MDM2 in diabetic nephropathy, by DRC member Sharma and others in JCI (2016). Sharma and colleagues show downregulation of MDM2 gene expression in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from patients with diabetic nephropathy. In diabetic mice, chemical inhibition of MDM2 led to reduction in the number of podocytes, identifying an important functional role for MDM2 in glomeruli and tubules of the diabetic nephropathic kidney.
  2. The genetic architecture of NAFLD among inbred strains of mice by DRC member Lusis and others in eLIFE (2015). Genome-wide association studies of inbred mouse strains by Lusis and colleagues revealed three loci associated with hepatic TG accumulation. Analyses of transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.
  3. Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells, by DRC members Tontonoz, Young and othersin Cell (2018). Tontonoz and colleagues describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-Bare deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
  4. ER Stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P, by DRC members Karin, Saltiel, Loomba and Kaufman in Cell(2018). Whereas the onset of simple steatosis requires elevated de novolipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. Caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. These data show that Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases.