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Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis

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Alcohol and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1032))

Abstract

PNPLA3 variant rs738409 has been identified as important progression factor in patients with ALD and NAFLD, the most common liver diseases worldwide. These findings point towards similarities between metabolism of alcohol and fat with regard to the PNPLA3 gene. However, despite many efforts, neither the mechanisms of PNPLA3-related liver damage nor the physiological role of PNPLA3 are fully understood. Based on a large monocentric cohort of Caucasian heavy drinkers we could recently provide evidence that PNPLA3 GG primarily correlated with signs of liver damage (steatohepatitis, ballooning) but less with steatosis. Moreover, upon alcohol withdrawal, PNPLA3 GG carriers showed a delayed inflammation-associated resolution of liver stiffness. In line with the histological findings, hepatic fat content as quantified by CAP (controlled attenuation parameter) did not depend on PNPLA3 status and decreased equally in all genotypes by ca. 30 dB/m during alcohol withdrawal. Preliminary additional analysis from this large cohort indicates that PNPLA3 GG carriers (8.2%) drink significantly less high percentage beverages (23% vs 55%, p < 0.001) but show no metabolic phenotype such as increased weight, BMI or diabetes. On the molecular level, key molecules, important for lipolysis and flow of free fatty acids to the liver were drastically reduced in G carriers. These included the liver-synthesized serum ApoA1, the LD-associated protein perilipin5 and the recently identified hepato-protective transcriptional cofactor transducin beta-like-related 1 (TBLR1). Based on these findings, we here introduce the liver damage feedback hypothesis. Accordingly, PNPLA3-mediated liver damage (e.g. by enhanced metabolic activity) suppresses the mobilization of fat towards the liver at various levels (reduced serum lipid flux to the liver and fat mobilization from peripheric adipose tissues, suppressed hepatocyte fat release and avoidance of high percentage alcohol beverages). Finally, the liver damage feedback hypothesis identifies a novel and central role of liver damage on systemic fat homeostasis, which has not been appreciated so far.

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Authors and Affiliations

  1. Center for Alcohol Research, University Hospital Heidelberg and Salem Medical Center, Heidelberg, Germany

    Vanessa Rausch

  2. Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany

    Sebastian Mueller

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  1. Vanessa Rausch
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Correspondence to Vanessa Rausch .

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Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the US, Washington, DC, USA

    Samir Zakhari

  3. Mishra Laboratory, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Lopa Mishra

  4. Salem Medical Centre, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany

    Helmut K. Seitz

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Rausch, V., Mueller, S. (2018). Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis. In: Vasiliou, V., Zakhari, S., Mishra, L., Seitz, H. (eds) Alcohol and Cancer. Advances in Experimental Medicine and Biology, vol 1032. Springer, Cham. https://doi.org/10.1007/978-3-319-98788-0_12

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