An Inner Mitochondrial Membrane Microprotein from the SLC35A4 Upstream ORF Regulates Cellular Metabolism.

Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing downstream translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one of the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs were rarely studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functional microprotein (SLC35A4-MP) because of its conserved amino acid sequence. Through a series of biochemical and cellular experiments, we find that the 103-amino acid SLC35A4-MP is a single-pass transmembrane inner mitochondrial membrane (IMM) microprotein. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add SLC35A4-MP to the growing list of functional microproteins and, more generally, indicate that uORFs that encode conserved microproteins are an untapped reservoir of functional microproteins.

Suppression of Postprandial Blood Glucose Fluctuations by a Low-Carbohydrate, High-Protein, and High-Omega-3 Diet via Inhibition of Gluconeogenesis.

Hyperglycemia significantly contributes to the development and progression of metabolic diseases. Managing postprandial blood glucose fluctuations is of particular importance for patients with hyperglycemia, but safe and effective means of reducing blood glucose levels are still lacking. Five diets with varying macronutrient ratios and omega-3 fatty acid amounts were tested for their blood glucose-lowering effects in male C57BL/6J mice. The diets with potent blood glucose-lowering effects were further investigated for their underlying mechanisms and their beneficial effects on hyperglycemia models. Mice given the low-carbohydrate, high-protein, and high-omega-3 (LCHP+3) diet exhibited a rapid reduction of the blood glucose levels that remained consistently low, regardless of feeding. These effects were associated with reduced amino acid gluconeogenesis, due to the inhibition of hepatic alanine transaminase (ALT). Furthermore, the LCHP+3 intervention was effective in reducing the blood glucose levels in several disease conditions, including type 1 diabetes mellitus, hormone-induced hyperglycemia, and diet-induced metabolic syndrome. Our findings identify the LCHP+3 diet as a potent blood glucose-lowering diet that suppresses postprandial blood glucose fluctuations through the inhibition of gluconeogenesis and may have great clinical utility for the management of metabolic diseases with hyperglycemia.

Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids.

BACKGROUND: Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. METHODS: We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. RESULTS: We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). CONCLUSIONS: These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. GENERAL SIGNIFICANCE: Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution.

Transgenic mice convert carbohydrates to essential fatty acids.

Transgenic mice (named "Omega mice") were engineered to carry both optimized fat-1 and fat-2 genes from the roundworm Caenorhabditis elegans and are capable of producing essential omega-6 and omega-3 fatty acids from saturated fats or carbohydrates. When maintained on a high-saturated fat diet lacking essential fatty acids or a high-carbohydrate, no-fat diet, the Omega mice exhibit high tissue levels of both omega-6 and omega-3 fatty acids, with a ratio of ∼1∶1. This study thus presents an innovative technology for the production of both omega-6 and omega-3 essential fatty acids, as well as a new animal model for understanding the true impact of fat on human health.