Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia.

NAFLD is the predominant liver disorder in many developed and developing countries, affecting as much as a third of the United States population1. Characterized by abnormally high hepatic lipid accumulation, NAFLD is of particular importance because it can progress to more dangerous disorders including nonalcoholic steatohepatitis (NASH) and potentially fatal liver cirrhosis2. NAFLD is commonly associated with metabolic syndrome, hypercholesterolemia and hypertriglyceridemia, and is often observed in obese or diabetic individuals, those with poor eating habits, or people who have experienced rapid weight loss. In addition, people without these risk factors can also develop NAFLD, and the incidence and severity of the disease is influenced by a variety of genetic and epigenetic factors in addition to lifestyle and other environmental influences1. Sequence variants in six genes have been both linked to human NAFLD and independently validated (for review see1). The I148M variant in PNPLA3, which encodes patatin-like phospholipase domain-containing protein 3, is the major recognized genetic basis for NAFLD in human populations3. When the PNPLA3 I148M human NAFLD-associated polymorphism (rs738409) is overexpressed in mice, it results in triacyglycerol (TAG) accumulation. Similar results are obtained by targeted hepatic overexpression of wild-type PNPLA3 in mice, via increased TAG and fatty acid synthesis and impaired hydrolysis of TAG; a relative depletion of long-chain polyunsaturated forms of TAG was also observed4,5. The other five genes are GCKR (which regulates glucokinase activity and hepatic glucose intake)6; PEMT, a catalyst for phosphatidylcholine synthesis7; SOD2 (which clears mitochondrial reactive oxygen species and protects against cell death)8; KLF6 (a transcription factor that influences fibrogenesis)9; and ATGR1 (angiotensin type 1 receptor)10. In addition to these genetic factors and metabolic syndrome, hepatic iron also influences lipid metabolism and hepatic steatosis. Iron overload can cause oxidative stress and lipid peroxidation, and can, for example, increase the formation of intracellular lipid droplets in liver cells in vitro. Conversely, iron deficiency has been shown to increase lipogenesis in rat liver, resulting in triglyceride accumulation and steatosis11. Thus, NAFLD is a common and highly complex pathological state affected by many different interacting factors that can potentially influence its onset and development into more severe diseases. We previously found that targeted deletion of the Kcne2 gene causes iron deficiency anemia, and also hypercholesterolemia12. KCNE2 is a potassium channel β subunit linked to cardiac arrhythmias and atherosclerosis13,14,15. The five-strong KCNE gene family comprises single transmembrane span proteins (KCNE subunits, also referred to as Mink-related peptides or MiRPs) that co-assemble with and alter the functional attributes of voltage-gated potassium (Kv) channel pore-forming (α) subunits16. Like other KCNE subunits, KCNE2 is widely expressed in a variety of tissues, and can promiscuously associate with several different Kv α subunits17. Aside from its roles in cardiac myocytes, where KCNE2 regulates hERG, Kv4.2, Kv1.5 and Kv2.1 depending on the species13,18,19,20,21, KCNE2 also co-assembles with the KCNQ1 α subunit22. This complex is important for various epithelial tissues, including the stomach, thyroid and choroid plexus18,19,23,24. Importantly, Kcne2─/─ mice exhibit achlorhydria, because KCNQ1-KCNE2 channels are required for normal function of the parietal cell H+/K+-ATPase, and therefore gastric acid secretion24,25. Kcne2 deletion results in mis-trafficking of KCNQ1 channels to the basolateral side of parietal cells, where they cannot fulfil their normal function, and ultimately leads to gastritis cystica profunda and gastric neoplasia26,27. Because the Kcne2-linked achlorhydria impairs iron uptake and causes iron deficiency anemia, a potential cause of abnormalities in hepatic lipid metabolism, here we investigated Kcne2-dependent hepatic lipid content and transcriptome remodeling, and discovered that Kcne2 deletion causes NAFLD.