HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia

Davide Povero; Yongbin Chen; Scott M Johnson; Cailin E McMahon; Meixia Pan; Hanmei Bao; Xuan-Mai T Petterson; Emily Blake; Kimberly P Lauer; Daniel R O'Brien; Yue Yu; Rondell P Graham; Timucin Taner; Xianlin Han; Gina L Razidlo; Jun Liu

doi:10.1016/j.jhep.2023.03.041

HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia

J Hepatol. 2023 Aug;79(2):378-393. doi: 10.1016/j.jhep.2023.03.041. Epub 2023 Apr 13.

Authors

Davide Povero¹, Yongbin Chen², Scott M Johnson², Cailin E McMahon², Meixia Pan³, Hanmei Bao³, Xuan-Mai T Petterson⁴, Emily Blake⁵, Kimberly P Lauer⁵, Daniel R O'Brien⁵, Yue Yu⁵, Rondell P Graham⁶, Timucin Taner⁷, Xianlin Han⁸, Gina L Razidlo⁹, Jun Liu¹⁰

Affiliations

¹ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA; Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: povero.davide@mayo.edu.
² Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
³ Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Drive, San Antonio, TX 78229, USA.
⁵ Metabolomics Core, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
⁶ Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
⁷ Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
⁸ Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Departments of Surgery and Immunology, Mayo Clinic, Rochester, MN 55905, USA.
⁹ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA; Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
¹⁰ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA. Electronic address: liu.jun@mayo.edu.

PMID: 37061197
DOI: 10.1016/j.jhep.2023.03.041

Abstract

Background & aims: The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC.

Methods: The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpda^fl/fl) and hepatocyte-specific Hilpda knockout (Hilpda^ΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC.

Results: In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, Hilpda^ΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH.

Conclusions: Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target.

Impact and implications: Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.

Keywords: HILPDA; Hepatocellular carcinoma; Hypoxia; Nonalcoholic steatohepatitis; lipid metabolism; lipidomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Hepatocellular* / metabolism
Ceramides / metabolism
Disease Models, Animal
Fatty Acids / metabolism
Humans
Hypoxia / metabolism
Liver / pathology
Liver Neoplasms* / genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease* / complications
Non-alcoholic Fatty Liver Disease* / metabolism
Tumor Microenvironment

Substances

Ceramides
Fatty Acids
HILPDA protein, human
HIG2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding