Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

Abstract

Objective Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose. Methods The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study. Results Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition. Conclusions Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.

Exercise prevents fatty liver by modifying the compensatory response of mitochondrial metabolism to excess substrate availability

“…Current approaches for a pharmacological treatment of NAFLD include the development of inhibitors targeting acetyl-CoA carboxylase and fatty acid synthase at the level of fatty acid synthesis, the mitochondrial pyruvate carrier, and ketohexokinase, a key enzyme in the metabolism of fructose, which is a particularly potent driver of de novo lipogenesis [ 52 , 53 ]. By demonstrating that regular exercise can antagonize the upregulation of these factors or reduce their expression in mice fed a steatogenic diet, our results corroborate these intervention strategies.…”

The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease

“…Pharmacological inhibition of KHK activity with PF-06835919 is reported to prevent patients from hepatic steatosis, lipogenic, and fibrosis ( Shepherd et al, 2021 ). KHK deficiency or inhibition (PF-06835919) protects animals from fructose-induced obesity, insulin resistance, hypertriglyceridemia, and NAFLD ( Lanaspa et al, 2013 ; Futatsugi et al, 2020 ; Gutierrez et al, 2021 ). Knockout KHK could also decrease fructose-derived UA production and attenuate mitochondrial oxidative stress in mice ( Ishimoto et al, 2012 ).…”

Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, a First-In-Class Ketohexokinase Inhibitor for Metabolic Disorders and Nonalcoholic Fatty Liver Disease

“…PF-06835919 represents a first-in-class selective KHK inhibitor to have entered clinical trials for the treatment of metabolic disorders and NAFLD/NASH (Futatsugi et al, 2020). In early clinical studies, PF-06835919 was found to be safe and well-tolerated in healthy study participants, and dose-dependently increased plasma fructose indicative of KHK inhibition (Gutierrez et al, 2021;Kazierad et al, 2021). The present study characterizes the transport and metabolic pathways involved in the hepatic clearance of PF-06835919, and thus understand the primary drivers to its clinical PK and target tissue exposure.…”

“…All PBPK model parameters and the data source are listed in Table 4. Based on the clinical PK data (Gutierrez et al, 2021), observed CL h,Human was approximated from oral CL (CL/F) across a dose range (10-600 mg) assuming oral absorption is complete and first-pass extract is negligible [i.e., CL h,Human = (Dose/AUC -renal CL) = 0.32 ± 0.04 mL/min/kg]. Direct scaling of metabolic clearance alone, CL int,app , underpredicted human oral clearance by about 3-fold (Figure 4).…”

“…Upon oral ingestion, fructose is primarily metabolized by the intestines, followed by the liver, pancreas, and kidney (Ishimoto et al, 2012;Jang et al, 2018). Inhibition of KHK has been considered a promising therapeutic hypothesis for the treatment of metabolic diseases supported by studies in KHK-null mice, demonstrating protection from fructose induced hyperlipidemia, insulin resistance, obesity, and NAFLD (Ishimoto et al, 2012;Ishimoto et al, 2013) PF-06835919 was discovered as a first-in-class KHK inhibitor and has been evaluated in clinical trials for metabolic diseases and NAFLD/NASH (Futatsugi et al, 2020;Gutierrez et al, 2021). PF-06835919 is a highly selective inhibitor of KHK (two isoforms-A/C) in in vitro selectivity assays and showed no development-limiting findings in rat and dog toxicology studies (Futatsugi et al, 2020).…”