HDL biology
CETP-driven HDL lowering, unlike ApoE knockout, does not worsen muscle wasting in dysferlin-deficient mice (Lipids Health Dis 2024)
Original title: Apolipoprotein E knockout, but not cholesteryl ester transfer protein (CETP)-associated high-density lipoprotein cholesterol (HDL-C) lowering, exacerbates muscle wasting in dysferlin-null mice
While raising plasma total cholesterol via apolipoprotein E knockout drastically worsens muscle wasting in dysferlin-deficient (Dysf) mice, a model of limb-girdle muscular dystrophy type 2B, dysferlinopathy patients actually have abnormally low plasma HDL cholesterol, prompting researchers to test whether HDL-C lowering itself worsens the mild Dysf mouse phenotype. Human CETP, a plasma lipid transfer protein absent in mice, was overexpressed alone or with its adapter apolipoprotein B in Dysf mice fed a 2% cholesterol diet, which lowered HDL cholesterol by 54.5% and raised the cholesterol-to-HDL-C ratio by 181.3% without raising total cholesterol. Unlike the severe pathology seen in high-cholesterol Dysf/ApoE double knockout mice, CETP/ApoB-expressing Dysf mice showed no significant changes in ambulation, hanging capacity, muscle damage, collagen deposition, or fibre health, indicating that high cholesterol rather than low HDL cholesterol drives the muscular dystrophy phenotype in this model.
Original abstract
Background: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice.
Methods: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology.
Results: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage.
Conclusions: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.