The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease

Ohkubo, Rika; Mu, Wei-Chieh; Wang, Chih-Ling; Song, Zehan; Barthez, Marine; Wang, Yifei; Mitchener, Nathaniel; Abdullayev, Rasul; Lee, Yeong Rim; Ma, Yuze; Curtin, Megan; Srinivasan, Suraj; Zhang, Xingjia; Yang, Fanghan; Sudmant, Peter H.; Pisco, Angela Oliveira; Neff, Norma; Haynes, Cole M.; Chen, Danica

doi:10.1016/j.celrep.2022.111803

Cited by 8 publications

(4 citation statements)

References 65 publications

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“…8f ). Consistent with previous reports 58 , 59 , these observations support that NAD + depletion caused by increased mtDNA mutation burden decreases SIRT7 activity to regulate ISR. Taken together, these results indicate that mtDNA mutation burden causes intestinal aging through NAD + depletion, which activates ATF5-dependent ISR to inhibit Wnt/β-catenin signaling.…”

Section: Resultssupporting

confidence: 92%

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations

Yang,

Ruan,

Lin

et al. 2024

Nat Commun

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Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

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Section: Resultssupporting

confidence: 92%

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations

Yang,

Ruan,

Lin

et al. 2024

Nat Commun

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“…To identify potential central mediators of MASLD, we next conducted an interaction (hub gene) analysis including 235 genes (of the 237 unique genes), with nodes identifying genes with central relevance to MASLD ( Figure 2E ). Identified nodes included pathogenic mediators of hepatocyte regeneration and fibrosis regulation ( EGFR 23 , IGF-1 24 ), apoptosis regulation ( MET 25 ), inflammatory mediators ( CXCL2 26 , CRP , SERPINE1 ), extracellular matrix responses to hepatic injury ( VTN 27 , ACAN 28 ), glycogen metabolism ( PYGL 29 ), and mitochondrial pyruvate metabolism ( PKLR 30 , PC 31 ), among several other canonical markers of insulin sensitivity and adiposity ( ADIPOQ , INS ). These results suggested a predominant hepatic origin for the circulating MASLD proteome, implicating canonical metabolic-inflammatory-fibrotic pathways in liver degeneration.…”

Section: Resultsmentioning

confidence: 99%

“…We observed a very high enrichment of transcript expression of genes encoding the MASLD proteome in the liver (far beyond any other tissue), supportive of its hepatic origin. Moreover, identified protein targets specified broad pathways central to MASLD, including regulation of hepatocyte regeneration ( EGFR 23 ), injury, apoptosis ( MET 25 ), inflammation ( CXCL2 26 , CRP , SERPINE1 ), metabolism ( ACY1 6,11 , FAH 12 , ADH1A 13,14 , ALDOB, SORD 15 , AKR1D1 16 , AKR1C4 17,18 ), and fibrosis ( IGF-1 24 ). Given that these tissue references are from “normal” banks in bulk resolution (e.g., Human Protein Atlas/GTEX), we further explored our MASLD-associated proteomic targets at single nuclear and spatial resolution in human liver at an early MASLD stage 34 .…”

Section: Discussionmentioning

confidence: 99%

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver

Perry,

Hadad,

Chatterjee

et al. 2024

Preprint

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Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ~7000 proteins in ~5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized "liver-on-a-chip" model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic "liquid biopsy" of human liver relevant to clinical biomarker and mechanistic applications.

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“…The disorder usually manifests as hyperandrogenemia, irregular menstrual cycles, abnormal ovarian function, polycystic follicles (polycystic ovary syndrome), and insulin resistance (IR) [ 2 , 3 , 4 ]. Histologically, non-alcoholic fatty liver disease (NAFLD) is similar to alcoholic liver disease in terms of hepatic fat accumulation, in which patients do not drink alcohol or drink small amounts of alcohol [ 5 , 6 ]. The pathogenesis of NAFLD is multifactorial, but obesity and IR seem to be the key causative factors.…”

Section: Introductionmentioning

confidence: 99%

Icariin Alleviates Nonalcoholic Fatty Liver Disease in Polycystic Ovary Syndrome by Improving Liver Fatty Acid Oxidation and Inhibiting Lipid Accumulation

et al. 2023

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(1) Background: Icariin is the main component of the Chinese herb Epimedium. A number of studies have shown that it alleviates abnormal lipid metabolism. However, it is not clear whether and how icariin can ameliorate hepatic steatosis with polycystic ovary syndrome (PCOS). This study was designed to explore the anti-hepatosteatosis effect of icariin in rats with polycystic ovary syndrome. (2) Methods: Female Sprague Dawley(SD)rats were treated with a high-fat diet and letrozole for 21 days to make nonalcoholic fatty liver disease (NAFLD) in the polycystic ovary syndrome model. Then model rats were treated with icariin (by gavage, once daily) for 28 days. Serum hormones and biochemical variables were determined by ELISA or enzyme. RNA-sequence analysis was used to enrich related target pathways. Then, quantitative Real-time PCR (qRT-PCR) and Western blot were performed to verify target genes and proteins. (3) Results: Icariin treatment reduced excess serum levels of Testosterone (T), Estradiol (E2), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), LH/FSH ratio, insulin, triglycerides (TG), and aspartate aminotransferase (AST) in high-fat diet (HFD) and letrozole fed rats. Meanwhile, icariin ameliorated HFD and letrozole-induced fatty liver, as evidenced by a reduction in excess triglyceride accumulation, vacuolization, and Oil Red O staining area in the liver of model rats. Results of RNA-sequencing, western blotting, and qRT-PCR analyses indicated that icariin up-regulated fatty acid translocase (CD36), in mitochondria, and peroxisome proliferator-activated receptor α (PPARα) expression, which led to the enhancement of fatty acid oxidation molecules, such as cytochrome P450, family 4, subfamily a, polypeptide 3 (CYP4A3), carnitine palmitoyltransferase 1 α (CPT1α), acyl-CoA oxidase 1 (ACOX1), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD). Besides, icariin reduced lipid synthesis, which elicited stearoyl-Coenzyme A desaturase 1 (SCD1), fatty acid synthase (FASN), and acetyl-CoA (ACC). (4) Conclusion: Icariin showed an ameliorative effect on hepatic steatosis induced by HFD and letrozole, which was associated with improved fatty acid oxidation and reduced lipid accumulation in the liver.

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The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease

Cited by 8 publications

References 65 publications

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver

Icariin Alleviates Nonalcoholic Fatty Liver Disease in Polycystic Ovary Syndrome by Improving Liver Fatty Acid Oxidation and Inhibiting Lipid Accumulation

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