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.
AIMS: LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolaemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown. METHODS AND RESULTS: To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G vs. wildtype HL (HL-WT) in hypercholesterolaemic APOE3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr-/-) mice. APOE3.Leiden.CETP mice or Ldlr-/- mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3 × 1011 GC/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (-63% vs. control; -58% vs. HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (-98% vs. control; -97% vs. HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr-/- mice (-80% vs. control; -77% vs. HL-WT), and decreased atherosclerotic lesion size in the aortic root (-54% vs. control; -41% vs. HL-WT) and the aortic arch (-73% vs. control; -70% vs. HL-WT). CONCLUSIONS: HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolaemia.
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.
CONTEXT: The incidence of kidney cancer is rising in Korea, with lifestyle and metabolic factors such as smoking, obesity, and hypertension contributing to this trend. OBJECTIVE: This study assessed the relationship between diabetes progression and kidney cancer risk. METHODS: Using data from the National Health Information Database in South Korea, analyzing 2 365 294 patients with type 2 diabetes mellitus who underwent health examinations in 2015 and 2016, excluding those with pre-existing cancer or who died within a year. Patients were monitored until 2022 to determine the incidence of kidney cancer, defined by ICD-10 code C64. Diabetes progression was assessed using a scoring system (range 0-6) based on the number of oral glucose-lowering drugs (GLDs), diabetes duration, insulin use, and the presence of chronic kidney disease (CKD), diabetic retinopathy (DR), or cardiovascular disease. RESULTS: Among the indicators of diabetes progression, prolonged diabetes duration and the presence of CKD or DR were linked to higher hazard ratios (HRs) for kidney cancer. The risk of kidney cancer increased progressively with higher diabetes progression scores. Compared to participants with a score of 0, the adjusted HRs for kidney cancer were 1.21 (95% CI 1.13-1.30) for a score of 1, 1.28 (1.18-1.38) for a score of 2, 1.37 (1.23-1.51) for a score of 3, and 1.73 (1.49-2.01) for scores of 4 or higher. CONCLUSION: Diabetes progression is strongly associated with an increased risk of kidney cancer. These findings underscore the importance of targeted screening and awareness programs for kidney cancer in individuals with advanced diabetes.
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.
Obesity is a major risk factor for multiple metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). The cholesterol sulfotransferase SULT2B1 is best known for its function in converting cholesterol to cholesterol sulfate. Here, by using the high-fat diet (HFD)-induced obesity model and the genetic obese ob/ob mice, we showed that genetic ablation of Sult2b1 protected mice from developing obesity and related insulin resistance, hepatic steatosis, and adipose tissue inflammation. Loss of Sult2b1 increased energy expenditure without affecting food intake or locomotive activity. The cold exposure test revealed that loss of Sult2b1 promoted thermogenesis in brown adipose tissue, which may have contributed to increased energy expenditure. In vivo reconstitution experiments suggested that the loss of Sult2b1 in extrahepatic tissues might have been responsible for the metabolic benefit. Mechanistically, our in vivo lipid uptake and metabolomic analyses showed that the Sult2b1KO mice exhibited suppression of intestinal dietary lipid absorption and the consequent downregulation of both systemic fatty acid levels and fatty acid metabolism. Our results suggest that targeting SULT2B1 may represent a novel strategy to combat obesity and related metabolic syndrome.