Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating Aryl hydrocarbon Receptor-dependent AMPK signaling.

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by accumulation of fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance of hepatic Aryl hydrocarbon Receptor (AhR) signaling in cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers of high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific Aryl hydrocarbon Receptor knockout mice (AhR-hKO) exhibited aggravated steatosis, inflammation, and fibrosis compared to control AhR-floxed livers.

Acyl-CoA synthetase 6 controls rod photoreceptor function and survival by shaping the phospholipid composition of retinal membranes.

The retina is light-sensitive neuronal tissue in the back of the eye. The phospholipid composition of the retina is unique and highly enriched in polyunsaturated fatty acids, including docosahexaenoic fatty acid (DHA). While it is generally accepted that a high DHA content is important for vision, surprisingly little is known about the mechanisms of DHA enrichment in the retina.

The Spinocerebellar Ataxia 34-Causing W246G ELOVL4 Mutation Does Not Alter Cerebellar Neuron Populations in a Rat Model.

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant disease that arises from point mutations in the fatty acid elongase, Elongation of Very Long Chain Fatty Acids 4 (ELOVL4), which is essential for the synthesis of Very Long Chain-Saturated Fatty Acids (VLC-SFA) and Very Long Chain-Polyunsaturated Fatty Acids (VLC-PUFA) (28-34 carbons long). SCA34 is considered a neurodegenerative disease. However, a novel rat model of SCA34 (SCA34-KI rat) with knock-in of the W246G ELOVL4 mutation that causes human SCA34 shows early motor impairment and aberrant synaptic transmission and plasticity without overt neurodegeneration.

Novel Approaches for Elongation of Fish Oils into Very-Long-Chain Polyunsaturated Fatty Acids and Their Enzymatic Interesterification into Glycerolipids.

Elongation of the Very-Long-Chain Fatty Acids-4 (ELOVL4) enzyme that is expressed in neuronal tissues, sperm, and testes mediates biosynthesis of very-long-chain polyunsaturated fatty acids (VLC-PUFAs) from dietary long chain PUFAs (LC-PUFAs). The VLC-PUFAs are critical for neuronal and reproductive function. Therefore, mutations in ELOVL4 that affect VLC-PUFA biosynthesis contribute to retinal degenerative diseases including Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3).

Response of the Glutathione (GSH) Antioxidant Defense System to Oxidative Injury in Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a neonatal intestinal disease associated with oxidative stress. The targets of peroxidation and the role of the innate intestinal epithelial antioxidant defense system are ill-defined. We hypothesized that oxidative stress in NEC correlates with oxidized GSH redox potentials, lipid peroxidation, and a dysfunctional antioxidant system.

Synapse-Specific Defects in Synaptic Transmission in the Cerebellum of W246G Mutant ELOVL4 Rats-a Model of Human SCA34.

Elongation of very long fatty acids-4 (ELOVL4) mediates biosynthesis of very long chain-fatty acids (VLC-FA; ≥28 carbons). Various mutations in this enzyme result in spinocerebellar ataxia-34 (SCA34). We generated a rat model of human SCA34 by knock-in of a naturally occurring c.

Dietary protection against the visual and motor deficits induced by experimental autoimmune encephalomyelitis.

Introduction: Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of autoimmune-mediated demyelination that induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS).

Ablation of pigment epithelium-derived factor receptor (PEDF-R/Pnpla2) causes photoreceptor degeneration.

Photoreceptor cells express the patatin-like phospholipase domain-containing 2 (PNPLA2) gene that codes for pigment epithelium-derived factor receptor (PEDF-R) (also known as ATGL). PEDF-R exhibits phospholipase activity that mediates the neurotrophic action of its ligand PEDF. Because phospholipids are the most abundant lipid class in the retina, we investigated the role of PEDF-R in photoreceptors by generating CRISPR Pnpla2 knock-out mouse lines in a retinal degeneration-free background.

Sperm very long-chain polyunsaturated fatty acids: relation to semen parameters and live birth outcome in a multicenter trial.

Objective: To determine whether the levels of sperm very long-chain polyunsaturated fatty acids (VLC-PUFAs) are correlated with sperm parameters and the outcome of live birth after conventional therapy for unexplained infertility.

Design: Cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation randomized controlled trial.

Setting: Multicenter randomized controlled trial.

Analysis of Lipids, Fatty Acid, and Cholesterol in Membrane Microdomains.

The original concept that lipid and protein components are randomly distributed in cellular membranes has been challenged by evidence of compartmentalization of such components into discrete membrane microdomains (known as lipid rafts). The lipid microdomain hypothesis has generated significant controversy and rigorous inquiry to test the idea that such domains concentrate machinery to mediate cellular processes such as signaling, synaptic plasticity, and endocytosis. As such, a large number of studies have used biochemical, cell biological, and biophysical methodologies to define the composition of membrane microdomains in experimental contexts.

Transmembrane protein 135 regulates lipid homeostasis through its role in peroxisomal DHA metabolism.

Transmembrane protein 135 (TMEM135) is thought to participate in the cellular response to increased intracellular lipids yet no defined molecular function for TMEM135 in lipid metabolism has been identified. In this study, we performed a lipid analysis of tissues from Tmem135 mutant mice and found striking reductions of docosahexaenoic acid (DHA) across all Tmem135 mutant tissues, indicating a role of TMEM135 in the production of DHA. Since all enzymes required for DHA synthesis remain intact in Tmem135 mutant mice, we hypothesized that TMEM135 is involved in the export of DHA from peroxisomes.

A Bietti Crystalline Dystrophy Mouse Model Shows Increased Sensitivity to Light-Induced Injury.

Bietti crystalline corneo-retinal dystrophy (BCD) is an autosomal recessive inherited retinal dystrophy characterized by multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal atrophy and sclerosis. Blindness and severe visual damage are common in late-stage BCD patients. We generated a knockout mouse model to investigate the pathogenesis of BCD.

Pharmacokinetics and metabolism in mouse retina of bis-allylic deuterated docosahexaenoic acid (D-DHA), a new dry AMD drug candidate.

Docosahexaenoic acid (DHA; 22:6n-3) rich photoreceptors function in a highly oxidizing microenvironment. Lipid peroxidation and inflammation contribute to initiation and progression of eye diseases including age-related macular degeneration (AMD). Deuteration of DHA at the bis-allylic positions (D-DHA) increases its resilience to oxidative damage in vitro.

Selective Ablation of in Astrocytes Induces Sex-Specific Effects on Cognitive Function, d-Serine Availability, and Astrogliosis.

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer's disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age.

Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis.

Obesity promotes the development of osteoarthritis (OA). It is also well-established that obesity leads to excessive lipid deposition in nonadipose tissues, which often induces lipotoxicity. The objective of this study was to investigate changes in the levels of various lipids in mouse cartilage in the context of obesity and determine if chondrocyte de novo lipogenesis is altered.

Deuterated docosahexaenoic acid protects against oxidative stress and geographic atrophy-like retinal degeneration in a mouse model with iron overload.

Oxidative stress plays a central role in age-related macular degeneration (AMD). Iron, a potent generator of hydroxyl radicals through the Fenton reaction, has been implicated in AMD. One easily oxidized molecule is docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in photoreceptor membranes.

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver.

Maternal consumption of a high-fat, Western-style diet (WD) disrupts the maternal/infant microbiome and contributes to developmental programming of the immune system and nonalcoholic fatty liver disease (NAFLD) in the offspring. Epigenetic changes, including non-coding miRNAs in the fetus and/or placenta may also underlie this risk. We previously showed that obese nonhuman primates fed a WD during pregnancy results in the loss of beneficial maternal gut microbes and dysregulation of cellular metabolism and mitochondrial dysfunction in the fetal liver, leading to a perturbed postnatal immune response with accelerated NAFLD in juvenile offspring.

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34.

Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by ataxia and cerebellar atrophy. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is caused by mutations in ELOVL4 (ELOngation of Very Long-chain fatty acids 4), a fatty acid elongase essential for biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp.

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies.

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1.

Degradation of Photoreceptor Outer Segments by the Retinal Pigment Epithelium Requires Pigment Epithelium-Derived Factor Receptor (PEDF-R).

Purpose: To examine the contribution of pigment epithelium-derived factor receptor (PEDF-R) to the phagocytosis process. Previously, we identified PEDF-R, the protein encoded by the PNPLA2 gene, as a phospholipase A2 in the retinal pigment epithelium (RPE). During phagocytosis, RPE cells ingest abundant phospholipids and protein in the form of photoreceptor outer segment (POS) tips, which are then hydrolyzed.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice.