A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.

Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.