Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

Song, Xiaoyu; Wu, Wanfu; Dai, Yubing; Warner, Margaret; Nalvarte, Ivan; Antonson, Per; Varshney, Mukesh; Gustafsson, Jan-Åke

doi:10.3390/ijms241512461

Cited by 2 publications

(1 citation statement)

References 48 publications

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“…Such a sex difference may or may not be present in humans. Another potential explanation for the observed increased sensitivity to colitis only in male Hmgcs2 -null mice is the well-known protective effect of female sex steroids, particularly estrogen, against colonic inflammation [ 48 , 49 ]. In fact, the protective effects of estrogens against DSS-induced experimental colitis have been demonstrated in mice [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice

Bass,

Sivaprakasam,

Dharmalingam-Nandagopal

et al. 2024

Biochemical Journal

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Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.

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Section: Discussionmentioning

confidence: 99%

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice

Bass,

Sivaprakasam,

Dharmalingam-Nandagopal

et al. 2024

Biochemical Journal

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Targeting Liver X Receptors in Cancer Drug Discovery

Premaratne,

Bagchi,

Basu

et al. 2024

Receptors

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Liver X receptors (LXRs) are members of the nuclear receptor superfamily of ligand-dependent transcription factors. LXRα is predominantly expressed in metabolic tissues, whereas LXRβ is ubiquitously expressed. Upon ligand binding, they regulate the expression of target genes involved in lipid metabolism, cholesterol homeostasis, and immune responses, including those which function in pathways that are commonly reprogrammed during carcinogenesis. Known LXR ligands include oxysterols and natural and synthetic agonists which upregulate LXR transcriptional activity and target gene expression. Synthetic inverse agonists have also been identified that inhibit LXR activity. While both types of ligands have been shown to inhibit cancer cells and tumor growth either directly or indirectly by modulating the activities of stromal cells within the tumor microenvironment, they appear to target different aspects of cancer metabolism and other cancer hallmarks, including immune evasion. This review summarizes the characterization of LXRs and their ligands and their mechanisms of action in cancer models and discusses the future directions for translating these discoveries into novel cancer therapeutics.

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Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

Cited by 2 publications

References 48 publications

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice

Targeting Liver X Receptors in Cancer Drug Discovery

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