Abstract
Transient receptor potential canonical 5 (TRPC5), a calcium-permeable, non-selective cation channel is expressed in the periphery, but there is limited knowledge of its regulatory roles in vivo. Endogenous modulators of TRPC5 include a range of phospholipids that have an established role in liver disease, including lysophosphatidylcholine (LPC). Cholestasis is characterized by impairment of excretion of bile acids, leading to elevation of hepatic bile acids. We investigated the contribution of TRPC5 in a murine model of cholestasis. Wild-type (WT) and TRPC5 knock-out (KO) mice were fed a diet supplemented with 0.5% cholic acid (CA) for 21 days. CA-diet supplementation resulted in enlargement of the liver in WT mice, which was ameliorated in TRPC5 KO mice. Hepatic bile acid and lipid content was elevated in WT mice, with a reduction observed in TRPC5 KO mice. Consistently, liver enzymes were significantly increased in cholestatic WT mice and significantly blunted in TRPC5 KO mice. Localized dyslipidaemia, secondary to cholestasis, was investigated utilizing a selected lipid analysis. This revealed significant perturbations in the lipid profile following CA-diet feeding, with increased cholesterol, triglycerides and phospholipids, in WT, but not TRPC5 KO mice. Our results suggest that activation of TRPC5 contributes to the development of cholestasis and associated dyslipidemia. Modulation of TRPC5 activity may present as a novel therapeutic target for liver disease.
Highlights
Mammalian transient receptor potential (TRP) channels encompass over 28 members[1], and exert wide-ranging functions peripherally and centrally
TRPC1 and TRPC6 were identified to be functionally expressed in human liver, with a prominent role for TRPC6 in hepatic carcinoma, attributed to aberrant calcium signaling[12]; Transient receptor potential canonical 5 (TRPC5) commonly associates with TRPC12 and it is expressed at low levels in the liver[6]
We measured hepatic myeloperoxidase (MPO) activity, a marker of inflammatory leukocyte accumulation[21, 22], and found a significant increase in liver samples of WT Cholic acid (CA)-fed mice (P < 0.001). This increase in MPO activity was significantly diminished in TRPC5 KO mice (P < 0.01; Fig. 1e), indicative of reduced inflammation in these animals
Summary
TRPC5 deletion protects mice from cholestasis-induced liver injury. Consistent with previous reports[19, 20], CA supplementation of WT animals caused significant liver injury, characterised by increased serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, in addition to elevated liver weight (P < 0.01; Fig. 1a). CA-feeding resulted in a significant induction in the expression of LPCAT3 in WT mice (Fig. 4c) compared to control-fed mice (P < 0.05) This induction was not observed in TRPC5 KO mice, consistent with the attenuated hepatic lipid and TG content. While BA concentrations were reduced in CA-fed TRPC5 KO mice, we detected a significant repression of CYP7A1, the rate-limiting enzyme for the production of BAs from cholesterol[34] These results highlight the complex interplay in BAs and lipid homeostasis, and suggest that, 1) CA-induced dyslipidaemia is partially dependent on TRPC5 activity, while 2) CA-induced repression of CYP7A1, known to be dependent on FXR and other factors/mediators[35], is independent of TRPC5. These findings provide evidence that TRPC5 activation plays a causal role in the onset and development of cholestasis-induced liver pathology and may provide a novel therapeutic target
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