Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today. A hepatic lipase gain-of-function variant (HL-E97G) dramatically lowers cholesterol and atherosclerosis in mice via an LDL receptor–independent mechanism, suggesting a new therapeutic avenue for familial hypercholesterolemia. A Korean nationwide cohort (n=2.36 million) shows kidney cancer risk rises with diabetes progression, supporting risk-stratified screening, while SULT2B1 inhibition emerges as a promising anti-obesity target by boosting
Summary
Three impactful endocrinology studies stood out today. A hepatic lipase gain-of-function variant (HL-E97G) dramatically lowers cholesterol and atherosclerosis in mice via an LDL receptor–independent mechanism, suggesting a new therapeutic avenue for familial hypercholesterolemia. A Korean nationwide cohort (n=2.36 million) shows kidney cancer risk rises with diabetes progression, supporting risk-stratified screening, while SULT2B1 inhibition emerges as a promising anti-obesity target by boosting thermogenesis and reducing intestinal lipid absorption.
Research Themes
- LDLR-independent lipid lowering and atheroprotection
- Risk stratification for cancer in advanced diabetes
- Novel metabolic targets: thermogenesis and intestinal lipid absorption
Selected Articles
1. A rare gain of function variant of hepatic lipase attenuates hypercholesterolaemia and atherosclerosis in mice via an LDL receptor-independent mechanism.
In hypercholesterolemic mice, the hepatic lipase gain-of-function variant HL-E97G reduced plasma total cholesterol by up to 80% and markedly shrank aortic lesions, including in LDL receptor–deficient mice. Effects were linked to enhanced hepatic (V)LDL uptake, indicating an LDLR-independent lipid-lowering and anti-atherogenic mechanism.
Impact: This is the first in vivo demonstration that an HL phospholipase-biased variant can robustly lower cholesterol and atherosclerosis independently of LDLR, opening a therapeutic path for LDLR-deficient familial hypercholesterolemia.
Clinical Implications: Modulating hepatic lipase function (e.g., mimicking HL-E97G or targeted gene therapy) could benefit patients with familial hypercholesterolemia, including LDLR-null cases, but requires translational safety and efficacy studies.
Key Findings
- HL-E97G reduced plasma total cholesterol exposure by −63% vs control and −58% vs HL-WT in APOE*3-Leiden.CETP mice.
- Atherosclerotic lesion size in the aortic root decreased by −98% vs control (−97% vs HL-WT).
- In LDLR−/− mice, HL-E97G cut plasma cholesterol by −80% vs control and reduced aortic lesions (root −54%, arch −73%), indicating LDLR-independent efficacy.
- Mechanism included increased hepatic uptake of (V)LDL particles.
Methodological Strengths
- Use of two complementary mouse models (APOE*3-Leiden.CETP and Ldlr−/−) with pro-atherogenic diets.
- AAV8-mediated controlled gene expression enabling direct comparison of HL-WT vs HL-E97G with quantitative lipid and lesion assessments.
Limitations
- Preclinical mouse study; human translatability and long-term safety are unknown.
- AAV overexpression may not replicate physiological regulation of HL; detailed off-target effects were not assessed.
Future Directions: Develop pharmacologic modulators or gene-based strategies targeting HL activity; validate efficacy and safety in larger animals; dissect hepatic receptor pathways mediating enhanced (V)LDL uptake.
2. Diabetes Progression and Its Impact on Kidney Cancer Risk: Insights From a Longitudinal Korean Cohort Study.
In 2,365,294 South Korean adults with type 2 diabetes followed to 2022, kidney cancer risk increased stepwise with a diabetes progression score (adjusted HR up to 1.73 for score ≥4). Longer diabetes duration and presence of CKD or DR were key contributors.
Impact: This very large, nationwide cohort provides robust, graded risk estimates linking diabetes progression to kidney cancer, informing risk-stratified surveillance strategies.
Clinical Implications: Clinicians should consider targeted kidney cancer awareness and possibly enhanced imaging surveillance for patients with advanced diabetes (long duration, CKD, DR, insulin use/multiple GLDs).
Key Findings
- Nationwide cohort of 2,365,294 adults with T2DM showed stepwise increase in kidney cancer risk with higher diabetes progression scores.
- Adjusted HRs vs score 0: 1.21 (score 1), 1.28 (score 2), 1.37 (score 3), 1.73 (score ≥4).
- Longer diabetes duration and presence of CKD or DR were the strongest indicators associated with elevated kidney cancer risk.
Methodological Strengths
- Exceptionally large sample size with national coverage and longitudinal follow-up to 2022.
- Composite progression score capturing treatment intensity, complications, and duration, enabling graded risk stratification.
Limitations
- Administrative data with ICD-10 code definition may introduce misclassification; histologic subtypes unavailable.
- Residual confounding and generalizability beyond South Korea remain considerations.
Future Directions: External validation in other populations; evaluate cost-effectiveness and protocols for risk-based kidney cancer screening in advanced diabetes; investigate biologic mechanisms linking diabetic complications to renal carcinogenesis.
3. Inhibition of sulfotransferase SULT2B1 prevents obesity and insulin resistance by regulating energy expenditure and intestinal lipid absorption.
Genetic deletion of Sult2b1 prevented diet- and genetics-induced obesity, insulin resistance, hepatic steatosis, and adipose inflammation by increasing energy expenditure (enhanced BAT thermogenesis) and reducing intestinal lipid absorption, without altering food intake or activity.
Impact: Identifies SULT2B1 as a previously underappreciated regulator of systemic energy and lipid handling, offering a therapeutically tractable target for obesity and metabolic syndrome.
Clinical Implications: Pharmacologic inhibition of SULT2B1 could provide a dual-action therapy that boosts thermogenesis and limits lipid absorption to treat obesity and insulin resistance; target validation and safety profiling in humans are needed.
Key Findings
- Sult2b1 knockout protected HFD-fed and ob/ob mice from obesity, insulin resistance, hepatic steatosis, and adipose inflammation.
- Energy expenditure increased without changes in food intake or locomotor activity; cold exposure indicated enhanced brown adipose tissue thermogenesis.
- In vivo lipid uptake and metabolomics showed decreased intestinal dietary lipid absorption and reduced systemic fatty acid levels and metabolism.
- Reconstitution suggested extrahepatic Sult2b1 loss underlies metabolic benefits.
Methodological Strengths
- Use of both diet-induced and genetic (ob/ob) obesity models to establish robustness across etiologies.
- Integrated physiological, cold-challenge, lipid uptake, and metabolomic analyses to delineate mechanisms.
Limitations
- No pharmacologic SULT2B1 inhibitor tested; translational feasibility remains to be demonstrated.
- Sample sizes and long-term safety/compensatory pathways were not detailed.
Future Directions: Develop and test selective SULT2B1 inhibitors; define tissue-specific contributions; assess efficacy and safety in larger animal models and ultimately human studies.