Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in pa-tatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepa-tocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericel-lular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases

Method of analytic continuation for the inverse spherical mean transform in constant curvature spaces

The following problem arises in thermoacoustic tomography and has intimate connection with PDEs and integral geometry. Reconstruct a function f supported in an n-dimensional ball B given the spherical means of f over all geodesic spheres centered on the boundary of B. We propose a new approach to this problem, which yields explicit reconstruction formulas in arbitrary constant curvature space, including euclidean space ℝn, the n-dimensional sphere, and hyperbolic space. The main idea is analytic continuation of the corresponding operator families. The results are applied to inverse problems for a large class of Euler-Poisson-Darboux equations in constant curvature spaces of arbitrary dimension. © 2012 Hebrew University Magnes Press