Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues

Chai, Chofit; Rivkin, Mila; Berkovits, Liav; Simerzin, Alina; Zorde-Khvalevsky, Elina; Rosenberg, Nofar; Klein, Shoshana; Yaish, Dayana; Durst, Ronen; Shpitzen, Shoshana; Udi, Shiran; Tam, Joseph; Heeren, Joerg; Worthmann, Anna; Schramm, Christoph; Kluwe, Johannes; Ravid, Revital; Hornstein, Eran; Giladi, Hilla; Galun, Eithan

doi:10.1053/j.gastro.2017.08.013

Cited by 84 publications

(71 citation statements)

References 41 publications

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“…Our study suggests that NIK partly mediates the known function of miR-122 in lipid and cholesterol metabolism (45,46). Reduced levels of hepatic miR-122 have been reported in patients with nonalcoholic fatty liver disease (47).…”

Section: Discussionsupporting

confidence: 52%

Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

Lowey

Hertz

Chiu

et al. 2019

mBio

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Hepatitis C virus (HCV) harnesses host dependencies to infect human hepatocytes. We previously identified a pivotal role of IκB kinase α (IKK-α) in regulating cellular lipogenesis and HCV assembly. In this study, we defined and characterized NF-κB-inducing kinase (NIK) as an IKK-α upstream serine/threonine kinase in IKK-α-mediated proviral effects and the mechanism whereby HCV exploits this innate pathway to its advantage. We manipulated NIK expression in Huh7.5.1 cells through loss- and gain-of-function approaches and examined the effects on IKK-α activation, cellular lipid metabolism, and viral assembly. We demonstrated that NIK interacts with IKK-α to form a kinase complex in association with the stress granules, in which IKK-α is phosphorylated upon HCV infection. Depletion of NIK significantly diminished cytosolic lipid droplet content and impaired HCV particle production. NIK overexpression enhanced HCV assembly, and this process was abrogated in cells deprived of IKK-α, suggesting that NIK acts upstream of IKK-α. NIK abundance was increased in HCV-infected hepatocytes, liver tissues from Alb-uPA/Scid mice engrafted with human hepatocytes, and chronic hepatitis C patients. NIK mRNA contains an miR-122 seed sequence binding site in the 3′ untranslated region (UTR). miR-122 mimic and hairpin inhibitor directly affected NIK levels. In our hepatic models, miR-122 levels were significantly reduced by HCV infection. We demonstrated that HNF4A, a known transcriptional regulator of pri-miR-122, was downregulated by HCV infection. NIK represents a bona fide target of miR-122 whose transcription is downregulated by HCV through reduced HNF4A expression. This effect, together with the sequestering of miR-122 by HCV replication, results in “derepression” of NIK expression to deregulate lipid metabolism. IMPORTANCE Chronic hepatitis C virus (HCV) infection is a major global public health problem. Infection often leads to severe liver injury that may progress to cirrhosis, hepatocellular carcinoma, and death. HCV coopts cellular machineries for propagation and triggers pathological processes in the liver. We previously identified a pivotal role of IKK-α in regulating cellular lipid metabolism and HCV assembly. In this study, we characterized NIK as acting upstream of IKK-α and characterized how HCV exploits this innate pathway to its advantage. Through extensive mechanistic studies, we demonstrated that NIK is a direct target of miR-122, which is regulated at the transcription level by HNF4A, a hepatocyte-specific transcription factor. We show in HCV infection that NIK expression is increased while both HNF4A and miR-122 levels are decreased. NIK represents an important host dependency that links HCV assembly, hepatic lipogenesis, and miRNA biology.

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Section: Discussionsupporting

confidence: 52%

Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

Lowey

Hertz

Chiu

et al. 2019

mBio

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“…As a result of significant hepatocyte injury, most miR‐122 found in serum is passively leaked, much like GLDH and ALT. However, it has been shown that miR‐122 can be released from healthy hepatocytes and be taken up by tissues outside the liver, such as the kidneys and muscle, where it can induce important physiological changes …”

Section: Promising New Dili Biomarkersmentioning

confidence: 99%

“…However, it has been shown that miR-122 can be released from healthy hepatocytes and be taken up by tissues outside the liver, such as the kidneys and muscle, where it can induce important physiological changes. 74,75 This is not to say that miR-122 has no value as a DILI biomarker.…”

Section: Liver-specific Biomarkersmentioning

confidence: 99%

Serum biomarkers of drug‐induced liver injury: Current status and future directions

Church

Watkins

2018

J of Digest Diseases

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Drug‐induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data‐driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.

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“…Over the next decade, more and more miRNAs have been shown to regulate the synthesis and secretion of fatty acids and cholesterol. For example, miR‐122 (Chai et al, ), miR‐144(He et al, ), miR‐199a‐3p (Tan et al, ), miR‐20a/b (Liang et al, ), miR‐758‐5p (Li, Xia, et al, ).…”

Section: Introductionmentioning

confidence: 99%

Bta‐miR‐152 affects intracellular triglyceride content by targeting the UCP3 gene

Shen

Han

Wang

et al. 2019

Animal Physiology Nutrition

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According to our previous studies, bta‐miR‐152, PRKAA1 and UCP3 are differentially expressed in mammary gland tissues of high milk fat and low milk fat cows, and the trend in bta‐miR‐152 expression is opposite from those of PRKAA1 and UCP3. To further identify the function and regulatory mechanism of bta‐miR‐152 in milk fat metabolism, we investigated the effect of bta‐miR‐152 on cellular triglyceride content in bovine mammary epithelial cells cultured in vitro, on the basis of bta‐miR‐152 overexpression and inhibition assays. The target genes of bta‐miR‐152 were identified through qPCR, Western blotting and dual luciferase reporter gene detection. Compared with that in the control group, the expression of UCP3 was significantly lower in the bta‐miR‐152 mimic group, the expression of PRKAA1 was decreased, and the intracellular TAG content was significantly increased. After transfection with bta‐miR‐152 inhibitor, the expression of UCP3 increased significantly, and the expression of PRKAA1 decreased, but the difference was not significant; in addition, the intracellular TAG content decreased significantly. Therefore, we concluded that bta‐miR‐152 affects the intracellular TAG content by targeting UCP3.

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Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues

Cited by 84 publications

References 41 publications

Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

Serum biomarkers of drug‐induced liver injury: Current status and future directions

Bta‐miR‐152 affects intracellular triglyceride content by targeting the UCP3 gene

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