Tier 3 — preclinical

SIRT6 Mediates Sterol-Dependent Feedback Regulation of Cholesterol Biosynthetic Genes in Hepatocytes

Yeonsoo Kim, Ye Eun Cho, Hyeokjin Lim, Yunseo Park, Seonghwan Hwang
Biomolecules & Therapeutics 2026 34(5):1136-1147

Bibliography

PubMed
PMID 42676034
DOI
10.4062/biomolther.2026.046

Study snapshot

DesignCellular mechanistic study using human HepG2 and mouse AML12 hepatocytes.
ModelHepG2 and AML12 hepatocytes.
SampleCell experiments.
Intervention25-hydroxycholesterol, lovastatin, SIRT6 activators, SIRT6 inhibition and SIRT6 overexpression.
DurationAcute cell-culture experiments.
EndpointsSREBP2; HMGCR; HMGCS1; H3K9Ac; H3K56Ac; Cholesterol biosynthetic gene expression

What the study showed, in plain terms

SIRT6 acted as a nuclear sterol-responsive regulator in hepatocytes, translating cholesterol status into epigenetic repression of SREBP2-driven cholesterol biosynthetic genes.

Key findings

Sterol loading activated SIRT6-associated deacetylation and repressed cholesterol synthesis genes; SIRT6 inhibition reversed that repression, while SIRT6 activation opposed lovastatin-driven compensatory gene upregulation.

What this study can and cannot tell us

Cellular mechanistic evidence only; does not show that SIRT6 activators improve blood lipids, MASH or cardiovascular outcomes in humans.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability