(OR17-06-26) Long-Term Ketogenic Diet Intervention Induces Aquaporin-8 Upregulation, Hepatic Inflammation, and Oxidative Stress in ApoE Knockout Mice

Monday, July 27, 2026

11:30 AM - 11:42 AM ET

Location: Maryland Ballroom C

Presenting Author(s)

ZS

Zhihao Shi

Phd student
The Pennsylvania State University
Universty Park, Pennsylvania, United States

Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

Co-Author(s)

Id

Inês V. da Silva

Universidade de Lisboa, Portugal
KK

Karel Kalecký

Baylor Scott and White Research Institute, United States
DP

Devendra Paudel

The Pennsylvania State University, United States
AK

Anthony M. Koehle III

The Pennsylvania State University, United States
TN

Thomas Neuberger

The Pennsylvania State University, United States
RA

Ross AC

The Pennsylvania State University, United States
TB

Teodoro Bottiglieri

Baylor Scott and White Research Institute, United States
VS

Vishal Singh, PhD

Assistant Professor
The Pennsylvania State University
University Park, Pennsylvania, United States
GS

Graça Soveral

Universidade de Lisboa, Portugal
RC

Rita Castro

The Pennsylvania State University, United States

Disclosure(s):

Zhihao Shi: No relevant financial relationship(s) with ineligible companies to disclose.

Objectives: The ketogenic diet (KD) shows beneficial short-term effects, but its long-term metabolic consequences remain unclear. KD-induced nutritional ketosis alters energy metabolism and may affect mitochondrial redox balance. We hypothesized that aquaporin-8 (AQP8), a mitochondrial hydrogen peroxide channel, contributes to metabolic adaptation during prolonged KD exposure.

Methods: ApoE^−/− mice (model of metabolic dysregulation) were fed a KD(kcal%:CHO/fat/protein:2/80/18, n=8) or a control diet(CD,kcal%:CHO/fat/protein:70/11/18, n=7) for 12 weeks. Serum and metabolic organs [liver, white(WAT), and brown adipose tissue(BAT)] were collected for molecular, biochemical, and histological studies. Targeted metabolomics was performed on plasma and liver. Primary mouse hepatocytes (n=4) were treated with palmitic(PA) and oleic(OA) acids, the most abundant KD-fatty acids.

Results: KD-mice maintained similar body weight to CD-mice despite higher caloric intake. KD elevated systemic inflammation(IL-17, IFNγ, IL-1Ra) and activated catabolic pathways in WAT and BAT(Pgc1α, Cd137,Tnfα, Il-1β). Liver histology revealed steatosis with macrophage infiltration, while transcriptomic analysis indicated redox imbalance(Nox) and inflammation(Tnfα, Il-1β). Metabolomics showed that KD extensively remodeled hepatic and systemic metabolism, enriching polyunsaturated lipids while reducing antioxidant metabolites. Aqp8 expression was increased in liver, WAT, and BAT of KD-mice, and PA stimulation (but not OA) upregulated Aqp8 in primary hepatocytes.

Conclusions: The role of AQP8 in adaptation to long-term KD warrants further investigation.

Funding Sources: Wood-Whelan Research Fellowship to IVS