Matthew M Molusky

University of Michigan, Ann Arbor, Michigan, United States

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Publications (5)42.31 Total impact

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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder commonly associated with obesity. A subset of NAFLD patients further develops non-alcoholic steatohepatitis (NASH) that is characterized by chronic liver injury, inflammation, and fibrosis. Recent work has implicated the autophagy pathway in the mobilization and oxidation of triglycerides from lipid droplets. However, whether impaired autophagy in hepatocytes drives excess fat accumulation in the liver remains controversial. In addition, the role of autophagy in protecting the liver from gut endotoxin-induced injury has not been elucidated. Here we generated mice with liver-specific autophagy deficiency by conditional deletion of FIP200 (also called Rb1cc1), a core subunit of the mammalian ATG1 complex. To our surprise, mice lacking FIP200 in hepatocytes were protected from starvation- and high-fat diet-induced fat accumulation in the liver and had decreased expression of genes involved in lipid metabolism. Activation of the de novo lipogenic program by liver-X receptor was impaired in FIP200 deficient livers. Further, liver autophagy was stimulated by exposure to low doses of lipopolysaccharides (LPS) and its deficiency sensitized mice to endotoxin-induced liver injury. Together, these studies demonstrate that hepatocyte-specific autophagy deficiency per se does not exacerbate hepatic steatosis. Instead, autophagy may play a protective role in the liver following exposure to gut-derived endotoxins and its blockade may accelerate NASH progression.
    No preview · Article · Aug 2013 · Molecular Endocrinology
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    Matthew M Molusky · Di Ma · Katie Buelow · Lei Yin · Jiandie D Lin
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    ABSTRACT: Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. The 45-kDa isoform of ubiquitin-specific protease 2 (USP2-45) is a deubiquitinase that regulates hepatic gluconeogenesis and glucose metabolism. In this study, we found that USP2-45 is localized to peroxisomes in hepatocytes through a canonical peroxisome-targeting motif at its C-terminus. Clustering analysis indicates that the expression of a subset of peroxisomal genes exhibits robust diurnal rhythm in the liver. Despite this, nuclear hormone receptor PPARα, a known regulator of peroxisome gene expression, does not induce USP2-45 in hepatocytes and is dispensible for its expression during starvation. In contrast, a functional liver clock is required for the proper nutritional and circadian regulation of USP2-45 expression. At the molecular level, transcriptional coactivators PGC-1α and PGC-1β and repressor E4BP4 exert opposing effects on USP2-45 promoter activity. These studies provide insights into the subcellular localization and transcriptional regulation of a clock-controlled deubiquitinase that regulates glucose metabolism.
    Preview · Article · Nov 2012 · PLoS ONE
  • Di Ma · Siming Li · Matthew M Molusky · Jiandie D Lin
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    ABSTRACT: Nutrient and energy metabolism in mammals exhibits a strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. Recent work has demonstrated that autophagy is rhythmically activated in a clock-dependent manner. Because autophagy is a conserved biological process that contributes to nutrient and cellular homeostasis, its cyclic induction may provide a novel link between clock and metabolism. This review discusses the mechanisms underlying circadian autophagy regulation, the role of rhythmic autophagy in nutrient and energy metabolism, and its implications in physiology and metabolic disease.
    No preview · Article · Apr 2012 · Trends in Endocrinology and Metabolism
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    Matthew M Molusky · Siming Li · Di Ma · Lei Yu · Jiandie D Lin
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    ABSTRACT: Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis.
    Preview · Article · Mar 2012 · Diabetes
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    Carlos Hernandez · Matthew Molusky · Yaqiang Li · Siming Li · Jiandie D Lin
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    ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.
    Preview · Article · Oct 2010 · Cell metabolism

Publication Stats

88 Citations
42.31 Total Impact Points


  • 2012-2013
    • University of Michigan
      • Department of Cell and Developmental Biology
      Ann Arbor, Michigan, United States
  • 2010
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States