Abstract
N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is an experimental pharmaceutical and a steroidal liver X receptor (LXR) agonist, which does not induce undesired hepatic lipogenesis. Herein, DMHCA was evaluated for its retinal effects on normal C57BL/6J and Cyp27a1−/−Cyp46a1−/− mice; the latter having higher retinal total and esterified cholesterol in addition to retinal vascular abnormalities. Different doses and two formulations were used for DMHCA delivery either via drinking water (C57BL/6J mice) or by oral gavage (Cyp27a1−/−Cyp46a1−/− mice). The duration of treatment was 1 week for C57BL/6J mice and 2 or 4 weeks for Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, the higher DMHCA doses (37–80 mg/kg of body weight/day) neither increased serum triglycerides nor serum cholesterol but altered the levels of retinal sterols. Total retinal cholesterol was decreased in the DMHCA-treated mice, mainly due to a decrease in retinal unesterified cholesterol. In addition, retinal levels of cholesterol precursors lanosterol, zymosterol, desmosterol, and lathosterol were changed in Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, DMHCA effect on retinal expression of the LXR target genes was only moderate and gender-specific. Collectively, the data obtained provide evidence for a decrease in retinal cholesterol as a result of DMHCA acting in the retina as an enzyme inhibitor of cholesterol biosynthesis rather than a LXR transcriptional activator. Specifically, DMHCA appears to partially inhibit the cholesterol biosynthetic enzyme Δ24-dehydrocholesterol reductase rather than upregulate the expression of LXR target genes involved in reverse cholesterol transport. The identified DMHCA dosages, formulations, and routes of delivery as well as the observed effects on the retina should be considered in future studies using DMHCA as a potential therapeutic for age-related macular degeneration and diabetic retinopathy.
Highlights
The retina is a thin tissue that lines the back of the eye and responds to light by converting it into an electrical signal
We evaluated Cyp27a1−/−Cyp46a1−/− mice (Figures 5–7), which are on the C57BL/6J;129S6/SvEv background with total retinal cholesterol ∼1.5 times higher than that of wild-type mice on the C57BL/6J background
Retinal cholesterol excess in these animals is stored in the form of cholesterol esters, and their retinas have a number of pathologies (Saadane et al, 2014, 2016)
Summary
The retina is a thin tissue that lines the back of the eye and responds to light by converting it into an electrical signal. The retina is very small: only 1204 mm in humans and 15.6 mm in mice (Remtulla and Hallett, 1985; Panda-Jonas et al, 1994), a size that makes pharmacological investigations of the retina challenging. Lowering of cholesterol in the retina is one of the approaches that are currently under investigation for treatment of age-related macular degeneration (Pikuleva and Curcio, 2014), a common eye disease leading to vision loss in the elderly of industrialized countries. The majority (72%) of retinal cholesterol (at least in mice) is provided by local biosynthesis, which proceeds via the Bloch and Kandutsch-Russell pathways (Figure 1); the remaining 28% of cholesterol are taken up from the systemic circulation (Saadane et al, 2014; Lin et al, 2016). Small amounts of cholesterol excess stay in the retina in the form of cholesterol esters (Bretillon et al, 2008; Saadane et al, 2016)
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