Scope: Conjugated linoleic acid (CLA), a bioactive substance predominantly found in ruminant products, improves insulin resistance and exhibits anti-inflammatory activity. The chief objective of the study is to investigate the effects and potential mechanisms of CLA on high fructose-induced hyperuricemia and renal inflammation. Methods and results: Hyperuricemia and renal inflammation are induced in rats by 10% fructose. Hyperuricemia, insulin resistance, and renal inflammation are evaluated. CLA potently ameliorates fructose-induced hyperuricemia with insulin resistance and significantly reduces the levels of inflammation factors in serum and kidney. It reverses fructose-induced upregulation of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in the kidney. Moreover, CLA dramatically inhibits the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Additionally, CLA suppresses toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling activation to inhibit nuclear factor-kB (NF-kB) signaling in the kidney of fructose-fed rats. Conclusion: CLA ameliorates hyperuricemia along with insulin resistance and renal inflammatory, which may be associated with the suppression of renal GLUT9 and URAT1 in fructose-fed rats. Its molecular mechanism may be related to the inhibition of NLRP3 inflammasome and TLR4/MyD88 signaling pathway. Therefore, CLA may be a promising candidate for preventing fructose-induced hyperuricemia and renal inflammation.
Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca2+ binding and luminal Ca2+-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl–]ER and [K+]ER and ER morphology and regulates ER Ca2+ homeostasis, including internal Ca2+ release and steady-state [Ca2+]ER. ALS-associated mutant forms of CLCC1 increase steady-state [Cl–]ER and impair ER Ca2+ homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies.
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