Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS. RNA-seq with three biological replicates of synchronized wild type N2 and mutant alh-4(-) worms at the L4 stage to determine the differentially expressed genes.

细胞内脂肪醛的水平受到严格调控，以最大程度减少细胞组分形成毒性醛加合物。据此，脂肪醛脱氢酶（FALDH）的缺失会导致人类罹患斯约格伦-拉松综合征（SLS）。然而，目前学界对细胞应对未被清除的高水平脂肪醛的应答机制仍知之甚少。基于脂质组学与成像分析结果，本研究发现：定位于内质网、线粒体与过氧化物酶体的秀丽隐杆线虫脂肪醛脱氢酶同源基因ALH-4缺失后，线虫体内脂肪醛水平升高，且脂肪储存量降低。肠道中ALH-4的缺失会以细胞非自主的方式，诱导依赖于NHR-49/NHR-79的皮下过氧化物酶体增殖。转录组测序（RNA-seq）结果显示，该过程伴随过氧化氢酶与脂肪酸分解代谢酶的表达上调。此类应答是对抗ALH-4缺失所必需的，因为alh-4; nhr-49双突变体线虫无法存活。本研究揭示了脂肪醛水平相关的意外组织间通讯机制，并提示将过氧化物酶体增殖的药理学调控作为斯约格伦-拉松综合征的潜在治疗策略。本研究针对同步化培养的野生型N2线虫与alh-4(-)突变体线虫，在其L4发育期设置三组生物学重复，开展RNA测序以鉴定差异表达基因。