Accepted Preprint (first posted online 20 April 2017)

    Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

    1. Benjamin Jennings Renquist
    1. C Geisler, Animal and Comparative Biomedical Science, University of Arizona, Tucson, United States
    2. B Renquist, Animal Science, University of Arizona, Tucson, 85719, United States
    1. Correspondence: Benjamin Renquist, Email: bjrenquist{at}


    Fatty liver can be diet, endocrine, genetic, viral, or drug induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic, and ketogenic genes, promoting hyperglycemia, hyperlipidemia, and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency, and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis, and lipid export. Hepatic lipid accumulation may be induced through 4 separate mechanisms: 1) increased hepatic uptake of circulating fatty acids, 2) increased hepatic de novo fatty acid synthesis, 3) decreased hepatic beta-oxidation, and 4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation, and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

    • Received 14 October 2016
    • Received in final form 10 April 2017
    • Accepted 20 April 2017
    • Accepted Preprint first posted online on 20 April 2017

    This Article

    1. J Endocrinol JOE-16-0513
    1. Abstract
    2. All Versions of this Article:
      1. JOE-16-0513v1
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