Abstract
Two parallel pathways produce cholesterol: the Bloch and Kandutsch-Russell pathways. Here we used stable isotope labeling and isotopomer analysis to trace sterol flux through the two pathways in mice. Surprisingly, no tissue used the canonical K-R pathway. Rather, a hybrid pathway was identified that we call the modified K-R (MK-R) pathway. Proportional flux through the Bloch pathway varied from 8% in preputial gland to 97% in testes, and the tissue-specificity observed in vivo was retained in cultured cells. The distribution of sterol isotopomers in plasma mirrored that of liver. Sterol depletion in cultured cells increased flux through the Bloch pathway, whereas overexpression of 24-dehydrocholesterol reductase (DHCR24) enhanced usage of the MK-R pathway. Thus, relative use of the Bloch and MK-R pathways is highly variable, tissue-specific, flux dependent, and epigenetically fixed. Maintenance of two interdigitated pathways permits production of diverse bioactive sterols that can be regulated independently of cholesterol.
Highlights
Cholesterol is an essential structural component of vertebrate cell membranes (Maxfield and Tabas, 2005) and a precursor of vital end products such as bile acids (Russell, 2009) and steroid hormones (Sih and Whitlock, 1968)
The Bloch and K–R pathways were described more than 50 years ago and are widely accepted as the two major pathways for cholesterol synthesis (Kandutsch and Russell, 1960b; Bloch, 1965)
None of the tissues examined in this study had a pattern of sterol turnover consistent with the reaction sequence proposed by Kandutsch and Russell (1960b) (Figure 1, red arrows)
Summary
Cholesterol is an essential structural component of vertebrate cell membranes (Maxfield and Tabas, 2005) and a precursor of vital end products such as bile acids (Russell, 2009) and steroid hormones (Sih and Whitlock, 1968). Bloch et al (1965) proposed that reduction of the double bond in the side chain (Δ24) is the last reaction in the pathway (Figure 1, black arrows). Kandutsch and Russell (Kandutsch and Russell, 1960a, 1960b) reported that the preputial glands of mice synthesized dihydrolanosterol and other side-chain saturated intermediates that were different from those in the Bloch pathway. They proposed an alternative pathway, the Kandutsch–Russell (K–R) pathway, in which the Δ24 bond of lanosterol is reduced and the conversion of dihydrolanosterol to cholesterol proceeds via 7-dehydrocholesterol (Figure 1, red arrows) using the same enzymes as Mitsche et al eLife 2015;4:e07999.
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