SULT-Mediated Lipid Sulfation and the LXR/SREBP-1c Axis: Defining a Sulfur Flux Subtype of Treatment-Resistant Obesity/Adiposity-Based Chronic Disease (ABCD)

Treatment-resistant obesity/adiposity-based chronic disease (ABCD), affecting approximately 20-30% of cases, poses a significant challenge beyond traditional insulin resistance, often manifesting with preserved insulin sensitivity in early stages. This review driven hypothesis proposes that SULT-mediated lipid sulfation, via enzymes like SULT1A1, SULT1E1, and SULT2B1, drives this phenotype through LXR/SREBP-1c activation, enhancing de novo lipogenesis and inducing lipolysis resistance without compromising insulin's anabolic function. Upregulated SULTs catalyze PAPS-dependent sulfation of sterols and fatty acids, yielding metabolites such as cholesterol sulfate that serve as LXRα agonists, upregulating SREBP-1c to amplify FASN and ACACA expression, thereby increasing triglyceride synthesis by approximately 40%. Concurrently, sulfated lipids stabilize perilipins on droplet surfaces, electrostatically repelling ATGL and HSL to reduce non-esterified fatty acid release by approximately 50%, while mitochondrial integration impairs CPT1 and ETFDH, attenuating β-oxidation by approximately 30%. Endocrine perturbations, including T3/T4 sulfation that diminishes DIO2 affinity and lowers basal metabolic rate, synergize with intact insulin signaling to sustain depot stability, distinguishing this from conventional ABCD's reversible TAG cycling and IRS desensitization. Supporting evidence includes SULT1A1 knockouts conferring approximately 10-15% weight reduction and UCP1 elevation, SULT2B1 inhibition preventing high-fat diet-induced ABCD via enhanced energy expenditure, and human lipidomics showing elevated cholesterol sulfate correlating with BMI. MHO phenotypes, with preserved glucose tolerance despite high adiposity, underscore the novelty, as do high-starch diet models exhibiting ABCD sans glucose intolerance, addressing a gap in proving fully hyper-functional insulin in resistant scenarios. Plasma cholesterol sulfate emerges as a diagnostic biomarker for stratifying resistant cases. Novel sulfur-based interventions including sulfatase activators, taurine, molybdenum, thiol antioxidants, and steroid desulfators, modulate lipid sulfation pathways to enhance β-oxidation, mobilize NEFAs, suppress adipogenesis, and restore endocrine balance. This represents the first hypothesis linking lipid sulfation to treatment-resistant ABCD, independent of insulin resistance.