Citations

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

Ezetimibe inhibits intestinal cholesterol absorption and lowers low‐density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging‐derived proton density‐fat fraction (MRI‐PDFF) and liver histology in patients with biopsy‐proven NASH. In this randomized, double‐blind, placebo‐controlled trial, 50 patients with biopsy‐proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI‐PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two‐dimensional and three‐dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI‐PDFF (mean difference between the ezetimibe and placebo arms ‐1.3%, P = 0.4). Compared to baseline, however, end‐of‐treatment MRI‐PDFF was significantly lower in the ezetimibe arm (15%‐11.6%, P < 0.016) but not in the placebo arm (18.5%‐16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two‐dimensional and three‐dimensional magnetic resonance elastography‐derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI‐PDFF (‐4.35 ± 4.9% versus ‐0.30 ± 4.1%, P < 0.019). Conclusions : Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI‐PDFF‐derived fat maps and magnetic resonance elastography‐derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH. (H epatology 2015;61:1239–1250)